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1
Terrades, Garcia Nekane. "Interleukin-6 (IL-6)/IL-6 receptor and persistence of inflammation in Giant Cell Arteritis. Effects of IL-6 receptor blockade with tocilizumab." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/668038.
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Giant cell arteritis (GCA) is a chronic granulomatous vasculitis affecting large- and medium-sized vessels. This disease can lead to different symptoms related to vascular or systemic inflammation, such as fever and visual loss, and its exact etiology remains to be elucidated. Current treatment of GCA patients is based on glucocorticoids administration. However, not all patients respond properly to this treatment and the disadvantages associated to glucocorticoids promotes the search for new therapeutic alternatives.
Blockade of IL-6 signaling with tocilizumab (TCZ), a humanized monoclonal antibody against IL-6 receptor (IL-6R), represents a newly promising alternative, supported by the results of two recently published clinical trials. However, beyond its implication in the acute phase response, the role of IL-6 in the pathogenesis of GCA and vascular inflammation is still unknown. GCA patients treated with TCZ also showed a decrease of acute-phase proteins, which are usually used to monitor disease activity. Therefore, the utilization of this monoclonal antibody remarks the urgency to find alternative biomarker not directly related with IL-6 signaling to monitor GCA patients treated with TCZ.
Considering all this information, the aim of this doctoral thesis was to better understand the role of IL-6 in GCA pathogenesis as well as the impact of IL-6R blockade with TCZ. In addition, we aimed to test the potential of osteopontin (OPN) as a biomarker of disease activity in patients treated with this monoclonal antibody.
The results from the present study show that IL-6 and IL-6R are remarkably increased in temporal artery lesions from GCA patients compared with control arteries. Co-culture experiments suggest that vascular smooth muscle cells (VSMC) may be an important source of IL-6. IL-6R was found upregulated in GCA lesions, particularly at the granulomatous areas. Co-culture experiments supported this result since IL-6R protein expression was increased in mononuclear cells when co-cultured with VSMC. Contrary to what was observed in tissue, serum levels of sIL-6R showed no differences between GCA patients and controls.
The artery culture model was used to better understand the impact of TCZ. IL-6R blockade resulted in a significant decrease in the mRNA expression of STAT3 and SOCS3 after 5 days in culture. However, phosphorylation levels of STAT3 were not modified by TCZ treatment. Co-culture results suggest that under inflammatory conditions the inhibitory effect of TCZ on STAT3 activation may be partially compensated by alternative mechanisms.
IL-6R blockade with TCZ also decreased CCL2 and increased the expression of CXCL9 and CXCL10 in cultured temporal arteries. Based on in vitro results, IL-6R blockade may promote an upregulation of CXCL9 and CXCL10 expression in mononuclear cells, that may explain the increased expression observed in cultured arteries. The upregulation of this chemokines may be due to an increase in STAT1 expression and activation after TCZ treatment. IL-6R blockade with TCZ also induced a reduction in the adhesion and migratory capacity of mononuclear cells. These results suggest that IL-6R blockade with TCZ may contribute to decrease tissue inflammation by limiting the advent of new
inflammatory cells. Further research is needed to better understand the molecules involved in TCZ modulation of these processes.
TCZ treatment of cultured arteries did not affect OPN expression in GCA lesions. Consistently, while levels of C-reactive protein (CRP) were virtually undetectable after IL- 6R blockade, serum concentration of OPN was similar in patients on glucocorticoid or TCZ maintained remission. All together, these data suggest that sOPN could be a useful biomarker of disease activity for TCZ treated patients. However, the role of sOPN needs to be further explored in larger studies with longitudinal cohorts.<br>L’arteritis de cèl·lules gegants (ACG) és una malaltia inflamatòria crònica d’etiologia desconeguda que afecta les arteries de mitjà i gran calibre. El tractament actual es basa en l’administració de glucocorticoides tot i que presenten efectes adversos i molts pacients experimenten recaigudes. Aquest fet promou la recerca de teràpies alternatives o complementaries. Recentment, s’han publicat els resultats de dos assajos clínics on s’ha vist que un nou fàrmac anomenat tocilizumab (TCZ), un anticòs que bloqueja el receptor de la IL-6 (IL-6R), podria ser una bona alternativa terapèutica per al pacients amb ACG. No obstant, el paper de la IL-6 en la patogènesi de l’ACG és encara desconegut. A més, l’ús del TCZ ha posat de manifest la necessitat de buscar biomarcadors alternatius als clàssicament utilitzats per monitoritzar els pacients, ja que el tractament amb aquest anticòs redueix l’expressió de les proteïnes de fase aguda, les quals són induïdes per la IL-6. Els objectius de la present tesi doctoral han estat per tant, entendre millor el paper de la IL-6 en l’ACG, així com estudiar l’impacte del bloqueig del IL-6R amb TCZ. Tanmateix, s’ha analitzat el potencial de l’osteopontiona (OPN) com a biomarcador alternatiu en pacients tractats amb aquest anticòs.
Els resultats del present estudi mostren que tant la IL-6 com el seu receptor es troben incrementats en les lesions de pacients amb ACG. El bloqueig del IL-6R amb TCZ té un efecte clar sobre l’expressió de les quimiocines CCL2, CXCL9 i CXCL10. A més, els resultats suggereixen que el tractament amb TCZ podria contribuir a disminuir la inflamació en els teixits al prevenir l’arribada de noves cèl·lules inflamatòries.
En relació al possible paper de l’OPN com a biomarcador en pacients tractats amb TCZ es va veure que els nivells de OPN en sèrum eren similar als dels pacients tractats amb glucocorticoides. Per contra, els nivells de proteïna C reactiva eren pràcticament indetectables en el grup de pacients tractats amb l’anticòs. En conjunt, els resultats mostren que l’OPN podria ser un bon biomarcador de l’activitat de la malaltia en pacients tractats amb TCZ.
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Fischer, Patrick. "Bedeutung der IL-6-Signaltransduktionsinhibitoren SHP2 und SOCS3 für die Desensitisierung des IL-6-Signalweges." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=980407699.
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Dawson, Charlotte Helen. "STAT 6 and IL-4 signalling." Thesis, University of Sheffield, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245716.
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Saramago, Eduardo Alves. "O hidrogênio molecular potencializa a hipotermia e previne a hipotensão e a febre durante a inflamação sistêmica induzida por LPS." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/17/17134/tde-07022019-140036/.
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O hidrogênio molecular (H2) exerce efeito antioxidante, anti-apoptótico e antiinflamatório. Nesse estudo testamos a hipótese que o H2 modula as mudanças cardiovasculares, inflamatórias e termorregulatórias na inflamação sistêmica (IS) induzida por lipopolissacarídeo (LPS) em diferentes doses (0,1 ou 1,5 mg/kg, intravenoso, induzindo IS moderada ou severa) em ratos machos Wistar (250-300 g). LPS ou salina foi injetada imediatamente antes do início dos 360 minutos de inalação do H2 (2% H2, 21% O2, balanceado com nitrogênio) ou ar ambiente (21% O2, balanceado com nitrogênio). A temperatura corporal (Tc) foi mensurada por datalogger pré-implantados na cavidade peritoneal. O H2 não causou mudança nos parâmetros cardiovasculares, inflamatórios e na Tc dos ratos controle (tratados com salina). Durante a IS moderada o H2 reduziu o surgimento das citocinas pró-inflamatórias no plasma (TNF-? e IL-6) enquanto causou um aumento da IL-10 plasmática (citocina anti-inflamatória) e preveniu a febre. Durante a IS severa o H2 potencializou a hipotermia e preveniu a febre e a hipotensão. Além disso, o H2 causou uma redução no surgimento das citocinas pró-inflamatórias (TNF-? e IL-1? do plasma) e prostaglandina E2 [(PGE2), no plasma e no hipotálamo], e um aumento da IL-10 plasmática. Esses dados são consistentes com o entendimento que o H2 atenua a febre na IS moderada e durante a IS severa potencializa a hipotermia, previne a hipotensão e exerce um efeito antiinflamatório forte o suficiente para prevenir a febre alterando a sinalização febrigênica e alterando a produção hipotalâmica de PGE2<br>Molecular hydrogen (H2) exerts anti-oxidative, anti-apoptotic, and anti-inflammatory effects. Here we tested the hypothesis that H2 modulates cardiovascular, inflammatory, and thermoregulatory changes in systemic inflammation (SI) induced by lipopolysaccharide (LPS) at different doses (0.1 or 1.5 mg/kg, intravenously, to induce mild or severe SI) in male Wistar rats (250-300 g). LPS or saline was injected immediately before the beginning of 360- minute inhalation of H2 (2% H2, 21% O2, balanced with nitrogen) or room air (21% O2, balanced with nitrogen). Deep body temperature (Tb) was measured by dataloggers preimplanted in the peritoneal cavity. H2 caused no change in cardiovascular, inflammatory parameters, and Tb of control rats (treated with saline). During mild SI, H2 reduced plasma surges of proinflammatory cytokines (TNF-? and IL-6) while caused an increase in plasma IL-10 (anti-inflammatory cytokine) and prevented fever. During severe SI, H2 potentiated hypothermia, and prevented fever and hypotension. Moreover, H2 caused a reduction in surges of proinflammatory cytokines (plasma TNF-? and IL-1?) and prostaglandin E2 [(PGE2), in plasma and hypothalamus], and an increase in plasma IL-10. These data are consistent with the notion that H2 blunts fever in mild SI, and during severe SI potentiates hypothermia, prevents hypotension and exerts anti-inflammatory effects strong enough to prevent fever by altering febrigenic signaling and ultimately down-modulating hypothalamic PGE2 production
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Denz, Ulrich. "Einfluss des IL-6-sIL-6R-Fusionsproteins Hyper-IL-6 auf die Leber nach hydrodynamischer Transfektion in vivo." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=973066008.
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Poe, Shaunta D. "Autocrine Effects of Catecholamines on Macrophage Release of Interleukin-6 (IL-6)." VCU Scholars Compass, 2006. http://hdl.handle.net/10156/1786.
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FURINI, Federica. "P2X7 receptor (P2X7R) in Systemic Lupus Erythematosus (SLE). Exploring a novel pathogenetic pathway." Doctoral thesis, Università degli studi di Ferrara, 2019. http://hdl.handle.net/11392/2487988.
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Introduzione. P2X7R è un recettore extracellulare ATP-dipendente coinvolto in processi
infiammatori e autoimmuni che agiscono principalmente attraverso l'attivazione dell'inflammasoma
NLRP3 e il rilascio di IL-1β, ed anche tramite processi implicati nella regolazione della
proliferazione dei linfociti e nell'apoptosi cellulare. Diverse osservazioni da modelli animali e studi
su paziente evidenziano un possibile collegamento tra l'asse P2X7R-NLRP3 e la patogenesi del
Lupus Eritematoso Sistemico (SLE). L'asse inflammasoma-P2X7R oltre alla produzione diretta di
IL-1b e IL-18, è coinvolto indirettamente nel rilascio di altre citochine implicate nella patogenesi di
SLE, come IL-6. Lo scopo di questo studio è di esplorare il ruolo di P2X7R e di NLRP3-
inflammasoma nel Lupus.
Metodi. Sono stati arruolati 48 pazienti con SLE, 16 con (SLE-S) e 32 senza (SLE-NS) anamnesi
positiva per sierosite e 20 soggetti di controllo sani (HC) abbinati per sesso ed età. Sono stati
raccolti dati demografici, clinici, terapeutici e misure di outcome. I livelli plasmatici di IL-1β e IL-6
sono stati valutati mediante ELISA. Le cellule mononucleate del sangue periferico (PBMC) sono
state isolate dal sangue venoso mediante sedimentazione a gradiente di Ficoll e impiegate come
segue: 1) valutazione dell'espressione di P2X7R e NLRP3 mediante RT-PCR; 2) determinazione
dell'attività P2X7R come incrementi dei livelli di Calcio intracellulare [Ca2 +]i indotti da Benzoyl
ATP (BzATP) usando la sonda fluorescente Fura2-AM; 3) isolamento di monociti / macrofagi e
valutazione del rilascio in vitro di IL-1β e IL-6 dopo stimolazione con lipopolisaccaride (LPS) e
BzATP, separatamente o in combinazione.
Risultati. I livelli plasmatici di IL-1β non sono risultati significativamente differenti nei pazienti
con SLE rispetto a HC mentre i livelli di IL-6 sono risultati più elevati in SLE rispetto a HC, in
modo significativo nei pazienti con storia di sierosite. Monociti / macrofagi isolati da pazienti affetti
da SLE rilasciavano quantità inferiori di IL-1β dopo stimolazione con BzATP, mentre il rilascio di
IL-6 è risultato significativamente aumentato in SLE-NS rispetto a entrambi i soggetti HC e SLE-S
dopo tutti i tipi di stimolazione. L'aumento di [Ca2 +]i dopo stimolazione con BzATP era
significativamente più basso nei PBMC di pazienti con SLE rispetto a PBMC da HC.
La RT-PCR ha mostrato una riduzione significativa del P2X7R e un'espressione NLRP3
significativamente aumentata nei pazienti rispetto a HC.
Conclusioni. I nostri dati indicano una ridotta espressione e funzione di P2X7R nei pazienti affetti
da SLE rispetto ai soggetti HC e, al contrario, aumento della segnalazione di IL-6. Le possibili
conseguenze della riduzione del P2X7R, principalmente sulla regolazione del network citochinico e
sulla proliferazione dei linfociti, dovranno essere ulteriormente approfondite così come il ruolo
dell'IL-6 come possibile obiettivo terapeutico, specialmente nei paziente con storia di sierosite.<br>Introduction. P2X7R is an extracellular ATP-gated receptor involved in inflammatory and autoimmune processes mainly acting through NLPR3-inflammasome activation and IL-1β release, also implicated in lymphocyte proliferation and cellular apoptosis. Several observations from animal models and patient’s studies highlight a possible link between P2X7R-NLRP3 axis and Systemic Lupus Erythematosus (SLE) pathogenesis. The P2X7R-inflammasome axis in addition to the direct production of IL-1 and IL-18, indirectly mediates the release of other cytokines implicated in the pathogenesis of SLE, such as IL-6. The aim of this study was to investigate the role of P2X7R and NLRP3-inflammasome in SLE.
Methods. 48 SLE patients, 16 with (SLE-S) and 32 without (SLE-NS) history of serositis, and 20 healthy control (HC) subjects matched for sex and age were enrolled. Demographic, clinical, therapeutic data and outcome measures were collected. IL-1β and IL-6 plasma levels were evaluated by ELISA. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood by Ficoll gradient sedimentation and employed as follows: 1) evaluation of P2X7R and NLRP3 expression by RT-PCR; 2) determination of P2X7R activity as Benzoyl ATP (BzATP)-induced [Ca2+]i increments using Fura2-AM fluorescent probe; 3) isolation of monocytes/macrophages and assessment of in vitro IL-1β and IL-6 release following stimulation with lipopolysaccharide (LPS) and BzATP, either separately or in combination.
Results. Plasma IL-1β levels were unmodified in SLE subjects respect to HC whereas IL-6 levels were higher in SLE than in HC, resulting significantly increased in SLE-S. Monocytes/macrophages isolated from SLE patients released lower quantities of IL-1β after stimulation with BzATP, whereas IL-6 release was significantly augmented in SLE-NS respect to both HC subjects and SLE-S after all types of stimulation. The [Ca2+]i increase following BzATP stimulation was significantly lower in PBMCs from SLE patients than in PBMCs from HC. RT-PCR showed significantly reduced P2X7R and significantly augmented NLRP3 expression in SLE patients.
Conclusion. Our data indicate reduced P2X7R expression and function in SLE patients compared with HC subjects and, conversely, increased IL-6 signaling. The possible consequences of reduced P2X7R, mainly on cytokines network deregulation and lymphocyte proliferation, will be further investigated as well as the role of IL-6 as a possible therapeutic target especially in lupus serositis.
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Correia, Josà Walter. "Polimorfismo -174g>C do gene de Interleucina-6 da Tuberculose Pulmonar." Universidade Federal do CearÃ, 2009. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=3567.
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nÃo hÃ<br>O objetivo do estudo foi investigar o perfil de produÃÃo de IL-6 em pacientes com tuberculose pulmonar ativa e avaliar o papel funcional do polimorfismo -174G>C do gene de IL-6 na produÃÃo sistÃmica desta citocina. Um total de 63 pacientes e 99 controles foi estudado, sendo 38 pacientes [25(65,8%) masculinos] e 63 controles [51 (81%) masculinos] para a dosagem de IL-6, enquanto, 42 pacientes [25 (60%) masculinos] e 79 controles [62(78,5%) masculinos] para o estudo do polimorfismo. Os pacientes foram selecionados dos centros de referÃncia da rede estadual de saÃde: Dona LibÃnia, Hospital de Messejana, Hospital de Maracanaà e Hospital Geral Dr. CÃsar Cals. O grupo controle foi selecionado no HEMOCE. Foi realizado teste de ELISA para a dosagem sÃrica de IL-6. O DNA genÃmico foi extraÃdo de sangue perifÃrico e o polimorfismo de IL-6 foi estudado por reaÃÃo de polimerase em cadeia utilizando iniciadores seqÃÃncia especÃficos. A dosagem sÃrica de IL-6 se mostrou elevada nos pacientes portadores de tuberculose em relaÃÃo aos controles (mediana = 4,3 pg/mL versus 0,5 pg/mL, p<0,001), porÃm nÃo exibiu diferenÃa entre os grupos de doentes sensÃveis e os resistentes ao tratamento especÃfico. Em relaÃÃo ao estudo funcional do polimorismo de IL-6, foi observado um robusto aumento dos nÃveis de IL-6 nos doentes portadores do genÃtipo GG (mediana=4,1 pg/mL, variaÃÃo 0,5-12,0 pg/mL), em relaÃÃo aos portadores dos genÃtipos GC e CC, sendo que nestes se observou uma expressÃo de IL-6 semelhante a dos controles (mediana=0,6 pg/mL, variaÃÃo 0,0-2,8 pg/mL), conferindo significÃncia estatÃstica com p=0,04. A relevÃncia deste estudo à mostrar in vivo o papel funcional do polimorfismo de IL-6 na tuberculose. Em conclusÃo, o genÃtipo GG de pacientes com tuberculose pulmonar ativa determina produÃÃo aumentada de IL-6.<br>The aim of this study was to investigate the profile of IL-6 production in patients with active pulmonary tuberculosis and to evaluate the functional role of polymorphism -174G>C in the systemic production of this cytokine. A total of 63 patients and 99 controls were studied. Among them 38 patients [25(65.8%) males] and 63 controls [51(81%) males] were studied for the IL-6 dosage. Moreover, 42 patients [25(60%) males] and 79 controls [62(78.5%) males] were studied for the -174G>C polymorphism. Patients were selected from Dona LibÃnia Center; Messejana Hospital, Maracanau Hospital and Dr. Cesar Cals General Hospital. The control group was selected from HEMOCE. An ELISA test was performed to measure IL-6 in peripheral blood. The genomic DNA was extracted from peripheral blood and IL-6 polymorphism was studied by polymerase chain reaction using sequence-specific primers. The IL-6 dosage showed an increase in patients with tuberculosis in relation to controls (An increase in IL6 dosage was found in patients with tuberculosis in relation to controls) (median= 4.3 pg/mL vs 0.5 pg/mL, p<0.001), but no difference was observed in drug-sensitive patients in comparison to drug-resistant ones. The genotype distribution showed no difference between patients and controls. In relation to the functional study, the IL-6 levels pointed out a significant increase in patients presenting GG genotype (median=4.1 pg/mL, range 0.5-12.0 pg/mL), in relation to GC and CC careers; these two latter genotypes presented similar IL-6 production as in healthy individuals with median=0.6 pg/mL, range 0.0-2.8 pg/mL, corroborating statistical significance with p=0.04. The relevance of this study is to show in vivo the functional role of IL-6 polymorphism in active pulmonary tuberculosis. Conclusion, the GG genotype in patients with pulmonary tuberculosis determines an increase in IL-6 systemic production.
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Pereira, Leonardo Costa. "A influência do treinamento excêntrico nos níveis séricos de IL-6 e no polimorfismo -174C/G da IL-6." reponame:Repositório Institucional da UnB, 2013. http://repositorio.unb.br/handle/10482/14374.
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Dissertação (mestrado)—Universidade de Brasília, Programa de Pós Graduação em Ciências da Saúde, 2013.<br>Submitted by Albânia Cézar de Melo (albania@bce.unb.br) on 2013-10-18T14:52:24Z
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2013_LeonardoCostaPereira.pdf: 2444559 bytes, checksum: 48bcb389fa8bc06f54c9921d742aa8fe (MD5)<br>Introdução: Com o crescente envelhecimento da população brasileira estratégias que possam contribuir para a manutenção da saúde desse grupo etário são de suma relevância. Assim, estudos que abordam a prática de treino físico e a influencia genética sobre as respostas geradas no organismo de idosos vêm sendo
desenvolvidos. Objetivo: A presente pesquisa teve por objetivo avaliar a relação do
polimorfismo do gene promotor -174 C/G da IL-6 sobre as respostas da IL-6
sistêmica e dano muscular após treinamento de força excêntrico em homens idosos. Metodologia: Foram determinados os níveis de CK e de IL-6 nos momento pré, 0 h, 3 h, 24 h, 48 horas pós treino excêntrico para homens idosos. Foram identificadas as frequências genicas do polimorfismo do gene promotor IL6 G-174C e foram analisadas as possíveis relações genéticas com os níveis séricos da IL-6 e CK nos diferentes momentos. Para determinação da frequência genotípica foi empregado o teste de Hardy-Weinberg. Para efeito de análise estatística os sujeitos foram divididos em dois grupos genotípicos GG e CC/CG. Os dados contínuos foram expressos em média e erro padrão. Para comparar as medidas de CK e IL-6 foi utilizada ANOVA. As correlações entre o polimorfismo do gene promotor -174 C/G da IL-6 e os resultados de CK, IL-6, lipidograma, idade, altura e composição corporal foram determinadas pelo teste T independente. Resultados: Não foram encontradas diferenças significativas entre os grupos genotípicos e as variáveis antropométricas (p>0,05), perfil lipídico (p>0,05) e CK em todos os momentos (p>0,05). Foram verificadas diferenças entre os níveis de IL-6 basais e pós treino para todos os momentos entre os grupos (p=0,029). Conclusão: O treino excêntrico influenciou na modulação de CK e IL-6 independentemente do Polimorfismo do gene promotor - 174 C/G da IL-6. ______________________________________________________________________________ ABSTRACT<br>Introduction: With the increasing aging of the Brazilian population, strategies that may contribute to the maintenance of the health of this age group are of supreme importance. Studies what approach the practice of physical training and the genetic influence on the responses generated in the body of the elderly are being developed. Objective: The present research purposed to assess the relationship between polymorphism of the gene promoter -174 C/G from IL-6 about the replies of systemic IL-6 and muscle damage after eccentric strength training in elderly men. Methodology: Were determined the CK and the IL-6 levels in pre moment, 0 h, 3 h, 24 h, 48 hours after eccentric training in elderly men. Were identified the gene frequencies of polymorphism of promoter gene IL6 G-174C and were analyzed the possible genetic relationships with serum levels of IL-6 and CK in different moments. For determination of the genotype frequency was employed the test of Hardy-Weinberg. For the purpose of statistical analysis the subjects were divided into two
genotypic groups GG and CC/CG. Continuous data were expressed as average and
standard error. To compare the measures of CK and IL-6 it was used ANOVA. The
correlations between the polymorphism of the gene promoter -174 C/G of IL-6 and
the results of CK, IL-6, lipidogram, age, height and body composition were determined by independent T test. Results: No significant differences were found between the genotypic groups and anthropometric variables (p>0,05), lipid profile
(p>0,05) and CK in every moment (p>0,05). Differences were found between the levels of IL-6 basal and after training for all moments about the groups (p=0,029). Conclusion: The eccentric training was influenced in the modulation of CK and IL-6 independently of polymorphism of the gene promoter -174 C/G from IL-6.
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Malchow, Sven [Verfasser]. "Impact of IL-6 classic- and IL-6 trans-signaling on Concanavalin A immune-mediated liver damage / Sven Malchow." Kiel : Universitätsbibliothek Kiel, 2010. http://d-nb.info/102000407X/34.
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OLIVEIRA, Jacqueline Flores de. "Níveis séricos de interleucinas IL-6 e IL-10 em indivíduos com transtorno de estresse pós-traumático em uma amostra de base populacional." Universidade Catolica de Pelotas, 2018. http://tede.ucpel.edu.br:8080/jspui/handle/jspui/691.
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Previous issue date: 2018-01-04<br>Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq#<br>#-2555911436985713659#<br>#600<br>Post-traumatic stress disorder (PTSD) is a psychiatric disorder with a prevalence of 8%
in the population throughout life. Recent studies have suggested that in PTSD there is the
activation of the immune system with the increase of inflammatory mediators, being able
to influence the affective behavior and development of comorbidities. Thus, this study
aimed to evaluate the serum levels of interleukins IL-6 and IL-10 in individuals with
PTSD in a population-based sample. This is a case-control study, nested in a populationbased
cross-sectional study involving 82 individuals aged 18-35 years living in the urban
area of the city of Pelotas / RS. All individuals diagnosed with PTSD were selected, who
were not diagnosed with major depressive disorder (MDD), did not report use of
psychiatric and anti-inflammatory medications, constituting a group of 41 individuals. Of
these, 41 other individuals with the same clinical characteristics of the previous group,
differentiated only because they did not have PTSD diagnosis, were matched by sex and
age, constituting a control group. Data were collected through a self-administered
questionnaire with sociodemographic questions and psychoactive substance use. The
Mini International Neuropsychiatric Interview was used for the diagnosis of PTSD and
MDD. After the interview, 10 mL of blood was collected. Serum levels of IL-6 and IL10
were measured by the ELISA technique using commercial kits. The group of
individuals with PTSD presented a statistically significant increase in the serum levels of
the pro-inflammatory cytokine IL-6 and anti-inflammatory IL-10 (p = 0.002) when
compared to the control group. The results presented here suggest that individuals with
PTSD may present an activation of the immune system and may be related to a
neuroinflammatory process and the development of several clinical complications.<br>O transtorno de estresse pós-traumático (TEPT) é um transtorno psiquiátrico com uma
prevalência de 8% na população ao longo da vida. Estudos recentes têm sugerido que no
TEPT há a ativação do sistema imune com o aumento de mediadores inflamatórios,
podendo influenciar no comportamento afetivo e desenvolvimento de comorbidades.
Assim, este estudo teve como objetivo avaliar os níveis séricos das interleucinas IL-6 e
IL-10 em indivíduos com TEPT em uma amostra de base populacional. Trata-se de um
estudo de caso-controle aninhado a um estudo transversal de base populacional,
envolvendo 82 indivíduos de 18 a 35 anos, residentes na zona urbana da cidade de
Pelotas/RS. Foram selecionados todos os indivíduos diagnosticados com TEPT, os quais
não foram diagnosticados com transtorno depressivo maior (TDM), não relataram uso de
medicações psiquiátricas e anti-inflamatórias, constituindo um grupo de 41 indivíduos.
Destes, outros 41 indivíduos com as mesmas características clínicas do grupo anterior,
diferenciado apenas por não ter diagnóstico de TEPT, foram pareados por sexo e idade,
constituindo um grupo controle. Os dados foram coletados através de um questionário
autoaplicável com questões sociodemográficas e usos de substâncias psicoativas. Para o
diagnóstico de TEPT e TDM foi utilizado o Mini International Neuropsychiatric
Interview. Após a entrevista foram coletados 10 mL de sangue. Os níveis séricos de IL -
6 e IL-10 foram mensurados através da técnica de ELISA, utilizando kits comerciais. O
grupo de indivíduos com TEPT apresentou um aumento estatisticamente significativo nos
níveis séricos da citocina pró-inflamatória IL-6 e anti-inflamatória IL-10 (p=0.002)
quando comparados ao grupo de indivíduos controle. Os resultados aqui apresentados
sugerem que indivíduos com TEPT podem apresentar uma ativação do sistema
imunológico, podendo estar relacionado com um processo a neuroinflamatório e o
desenvolvimento de diversas complicações clínicas.
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Мозгова, Юлія Анатоліївна, Юлия Анатольевна Мозговая та Yuliia Anatoliivna Mozghova. "Динаміка вмісту IL-4 та IL-6 при хронічному тонзиліті в дітей". Thesis, Сумський державний університет, 2013. http://essuir.sumdu.edu.ua/handle/123456789/32359.
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Хронічне запалення піднебінних мигдаликів є розповсюдженим захворюванням дитячого віку, що несприятливо впливає на зростаючий організм. На хронічний тонзиліт страждає більше 2-3% дітей раннього віку, 6-7% - дошкільного та 8-9% школярів.
При цитуванні документа, використовуйте посилання http://essuir.sumdu.edu.ua/handle/123456789/32359
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Cirocco, Robert E. "Cytokine analisys in atlantic bottlenose dolphins: molecular characterization of IL-4, IL-6, and IL-10." FIU Digital Commons, 2001. http://digitalcommons.fiu.edu/etd/2370.
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The health status of wild and captive Atlantic Bottlenose dolphins (Tersiops truncatis) is difficult to ascertain. Mass strandings of these animals have been attributed to pollutants, as well as bacterial infections. Using human Enzyme Linked Immuno-Assays (ELISA) for immunological cytokines, I measured soluble cytokine levels with respect to their health status. In a retrospective analysis of dolphin sera, there was a trend of higher cytokine levels in “sick” animals. I cultured dolphin lymphocytes in the presence of a mitogen (PHA), a super antigen (Staph-A), Lipopolysaccharide (LPS), and a calcium flux inducer (PMA). Levels of messenger RNA, from these cultured cells, were assayed with Polymerase Chain Reaction (PCR) using primers for the human cytokines IL-2, EL-4, IL- 6, IL-10, Tumor Necrosis Factor, and Interferon gamma. Only IL-4, IL-6, and IL-10 messages were obtained, inferring similar nucleotide homology to the human primer sequences. The PCR products were sequenced. Sixteen IL-4 sequences, twelve IL-6 sequences and seven IL-10 sequences were obtained and analyzed. Each cytokine exhibited the same nucleotide sequence in all dolphins examined. There was no difference in the cytokine profile in response to the various stimuli. The derived amino acid composition for each of the dolphin cytokines was used for molecular modeling, which showed that dolphin IL-4, IL-6, and IL-10 were structurally similar to the corresponding proteins of Perissodactyla.
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Woolley, Jane Alison. "The production, assessment and application of antibodies to human interleukin-6 (IL-6)." Thesis, Queen Mary, University of London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338809.
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Champa, Zachary J. "Modulation of IL-6 and IL-8 Expression in Ovarian Cancer Cells by a Small OrganicCompound." Ohio University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1460987166.
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Erta, Cañabate Maria. "Role of astrocytic IL-6 and IL-6R in normal physiology and neuroinflammation." Doctoral thesis, Universitat Autònoma de Barcelona, 2014. http://hdl.handle.net/10803/275952.
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La Interleucina 6 (IL-6) és una citocina altament multifuncional, amb moltes accions pleiotròpiques, considerada una de les principals citocines controlant el sistema immune i coordinant-lo amb els sistemes nerviós i endocrí. La IL-6 es produeix en molts tipus cel·lulars dins del sistema nerviós central (SNC) i al seu torn, múltiples cèl·lules hi poden respondre. Per tant, és necessari caracteritzar quina és la contribució específica de cada tipus cel·lular en el paper global de la IL-6, tant en condicions fisiològiques com patològiques. Com que els astròcits tenen una important resposta enfront la IL-6 i, a més, són un dels principals productors de IL-6, hem produït per primera vegada ratolins amb una deficiència de IL-6 específica als astròcits (ratolins Ast-IL-6 KO) i ratolins amb una supressió del receptor de IL-6 en astròcits (ratolins Ast-IL-6R KO). Els nostres resultats indiquen que IL-6 i IL-6R astrocitaris influeixen en la supervivència inicial, presumptament per mitjà de la mortalitat intrauterina, i que estan involucrats en diferents graus en el control del pes corporal en adults i en el comportament (activitat locomotora, ansietat, exploració, agressivitat, aprenentatge i memòria), entre d’altres. A més, per tal d’estudiar el seu paper durant la neuro-inflamació, hem usat el model animal àmpliament usat de l’Esclerosis múltiple, la encefalitis autoimmune experimental (EAE), i un model de lesió traumàtica en escorça encefàlica (criolesió) en ratolins Ast-IL-6 KO i Ast-IL-6R KO. En referència a la EAE, els resultats indiquen que la deficiència en IL-6 i IL-6R astrocitàries no prevé completament la simptomatologia típica de paràlisis ascendent de la EAE però que si que modifica la seva simptomatologia d’una manera diferent segons el sexe. En referència a la lesió traumàtica a l’escorça, resultats inicials suggereixen un paper de la deficiència de IL-6 astrocitària en la resolució de la lesió traumàtica.
En algunes ocasions, eliminar el IL-6R astrocitari imita el fenotip dels ratolins Ast-IL-6 KO, mentre que en altres casos s’observava el contrari, suggerint accions autocrines i paracrines de la IL-6 astrocitaria. Els nostres resultats indiquen importants funcions de la IL-6 i el IL-6R astrocitaris, en alguns casos totalment diferent d’aquelles que s’havien vist amb els animals IL-6 KO totals.
Finalment, com que la IL-6 és capaç de senyalitzar sense unir-se al receptor de membrana mIL-6R sinó unint-se al receptor soluble (sIL-6R) (trans-senyalització), és necessari estudiar la importància d’aquesta via en les accions de la IL-6 al SNC, la qual cosa s’ha fet en ratolins bigènics (GFAP-IL6/sgp130) amb expressió restringida als astròcits de IL-6 i d’un inhibidor específic de la trans-senyalitazació, el sgp130. El bloqueig de la trans-senyalització en SNC redueix varis dels efectes perjudicials que té la IL-6 en un model animal de neuroinflamació (ratolins GFAP-IL6) com la gliosis severa, alteracions vasculars, neurogènesis malmesa i neurodegeneració.<br>Interleukin-6 (IL-6) is a highly plurifunctional cytokine, with many pleiotropic actions, considered one of the main cytokines controlling the immune system and coordinating it with the nervous and endocrine systems. IL-6 is produced in multiple cell types in the central nervous system (CNS), and in turn many cells do respond to it. It is therefore important to ascertain which the contribution of each cell type is in the overall role of IL-6, during both physiological and pathological conditions. As astrocytes are major responders to IL-6 as well as one of the main CNS producers of IL-6, we have produced for the first time mice with astrocyte-derived IL-6 deficiency (Ast-IL-6 KO mice) and mice with deletion of IL-6 receptor in astrocytes (Ast-IL-6R KO mice). Our results indicate that astrocyte IL-6 system influenced the early survival, presumably due to intrauterine death, and was also involved to various degrees in the control of adult body weight and behavior (such as locomotor activity, anxiety, exploration, aggressiveness, learning and memory), among others. Also, in order to test its role during neuroinflammation, we studied an extensively used animal model of Multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), and a traumatic brain injury model (cryolesion) in Ast-IL-6 KO and Ast-IL-6R KO mice. Regarding EAE, results indicate that lack astrocytic IL-6 and IL-6R deficiency did not fully prevent EAE's prototypical ascending paralysis course but they modified its symptomatology in a gender-dependent manner. Regarding traumatic injury to the cortex, preliminary results obtained suggest a role of astrocytic IL-6 deficiency in traumatic brain injury resolution. In some occasions deleting IL-6R in astrocytes mimicked the phenotype of Ast-IL-6 KO mice, while in others the opposite was observed, suggesting autocrine and paracrine roles of astrocytic IL-6. Our results suggest important roles of the astrocyte IL-6 system, in some cases totally unexpected from previous results with animals with total deletion in IL-6 (IL-6 KO mice).
Finally, as IL-6 is able to signal without binding to the membrane bound mIL-6R but by binding to a soluble receptor (sIL-6R) (trans-signaling), it is necessary to assess the importance of this pathway in mediating IL-6 actions in CNS. Bigenic mice (GFAP-IL6/sgp130 mice) with astrocyte-targeted production of IL-6 and coproduction of the specific inhibitor of IL-6 trans-signaling, human sgp130 were studied. Blockade of trans-signaling in the CNS reduced many of the detrimental effects that IL-6 have in the GFAP-IL-6 mice model of neuroinflammation; such as the severity of the gliosis, vascular alterations, impaired neurogenesis and neurodegeneration.
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Dewolf-Pieuchot, Nicole. "L'Enfant de 6 ans et la lecture comment il pense, comment il apprend /." Lille 3 : ANRT, 1988. http://catalogue.bnf.fr/ark:/12148/cb37617548n.
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Sasser, Amy Kate. "The role of stromal fibroblasts and IL-6 in breast cancer progression." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1172866243.
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Harré, Eva-Maria. "Die Rolle von Interleukin-6 (IL-6) in der zentralnervös vermittelten Fieberentstehung der Ratte." Wettenberg : VVB Laufersweiler, 2003. http://deposit.d-nb.de/cgi-bin/dokserv?idn=968960545.
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Manjavachi, Marianne Neves. "Mecanismos envolvidos na hipernocicepção mecânica muscular induzida pela Interleucina-6 (IL-6) em camundongos." reponame:Repositório Institucional da UFSC, 2012. http://repositorio.ufsc.br/xmlui/handle/123456789/93523.
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Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia, Florianópolis, 2010<br>Made available in DSpace on 2012-10-24T23:37:57Z (GMT). No. of bitstreams: 1
278034.pdf: 787631 bytes, checksum: 4e1a362ea442a16afcf597e48553d44d (MD5)<br>O objetivo do presente estudo foi investigar os possíveis mecanismos e mediadores envolvidos na hipernocicepção mecânica muscular induzida pela administração intramuscular (i.m.) de IL-6, no músculo gastrocnêmio de camundongos. Foi demonstrado que a injeção i.m. de IL-6 (3, 6 ou 10 ng/sítio) reduziu significativamente o limiar da resposta mecânica de maneira dose e tempo (1 - 6 h) dependentes em camundongos. Este efeito foi associado com aumento do recrutamento de células inflamatórias, como avaliado através da coloração H&E, além das atividades das enzimas MPO e NAG, e também com o aumento dos níveis de citocinas pró-inflamatórias (TNF-?, IL-1? e KC). Além disso, camundongos nocaute para TNFR1-/-, ou ainda os animais pré-tratados com o antagonista seletivo CXCR2, SB225002, ou com os anticorpos anti-macrófago, anti-TNF-? ou anti-KC, e ainda com o antagonista para o receptor para IL-1 (IL-1ra) demonstraram redução significativa da hipernocicepção mecânica induzida pela IL-6. Ademais, o tratamento sistêmico com inibidores de mediadores inflamatórios, como indometacina, celecoxibe, SC560, ou guanetidina, também reduziram a resposta nociceptiva causada pela administração i.m. de IL-6. A participação de diferentes vias de sinalização intracelular também foi observada, uma vez que o pré-tratamento local com inibidores de fosfolipase A2 (PACOCF3), fosfolipase C (U73122), proteína quinase C (GF109203X), proteína quinase A (KT-5720), ou com fosfatidilinositol 3-quinase (AS605204), reduziram significativamente a hipernocicepção muscular induzida pela IL-6. Similarmente, o tratamento i.m. dos inibidores seletivos de p38 (SB203580), ERK (PD98059) ou JNK (SP60015) também inibiram a hipersensibilidade mecânica induzda pela IL-6. Ainda, ERK, JNK e p38 encontraram-se fosforiladas 5 minutos após a administração i.m. de IL-6. Estes resultados forneceram novas evidências que indicam papel relevante da IL-6 no desenvolvimento e na manutenção da hipernocicepção muscular em camundongos. Ainda, a hipersensibilidade mecânica muscular induzida pela parece promover ativação de células residentes, infiltração de células polimorfonucleares, produção de citocinas, prostanóides e liberação de aminas simpaticomiméticas e ativação de vias intracelulares, especialmente MAPKs.
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Lopes, Fernando Henrique Azevedo. "NÃveis sÃricos de interleucina-6 e polimorfismo - 174G>C em infecÃÃo latente pelo Mycobacterium tuberculosis." Universidade Federal do CearÃ, 2012. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=7533.
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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior<br>A interleucina-6 (IL-6) à uma importante citocina que exerce papel fundamental na imunopatogÃnese de diversas doenÃas infecciosas. O objetivo deste estudo foi investigar o nÃvel de produÃÃo sistÃmica de IL-6 e aferir o papel funcional do polimorfismo -174 G>C do gene dessa citocina em indivÃduos diagnosticados como portadores de infecÃÃo latente pelo Mycobacterium tuberculosis (ILTB). Para controle, foram utilizados dois grupos de comparaÃÃo: um deles composto por portadores de tuberculose pulmonar ativa (TB) e o outro formado por indivÃduos saudÃveis, doadores de sangue. O grupo ILTB foi composto por 15 indivÃduos, selecionados dentre os contactantes de portadores de TB pulmonar ativa, atendidos no Hospital SÃo Josà de DoenÃas Infecciosas e no Centro de SaÃde da FamÃlia AnastÃcio MagalhÃes. O grupo TB foi formado por 38 pacientes com TB pulmonar ativa, procedentes do Hospital de Messejana, Hospital de Maracanaà e Hospital Geral Dr. CÃsar Cals. O grupo de indivÃduos saudÃveis contava com 63 doadores voluntÃrios de sangue do Centro de Hematologia e Hemoterapia do CearÃ. A dosagem sÃrica de IL-6 foi realizada por meio de um ensaio imunoenzimÃtico (ELISA), com kit especÃfico fornecido pela Invitrogen Corporation. Para purificaÃÃo do DNA, foi utilizado o kit GFX Genomic Blood DNA Purification, da GE Healthcare. O polimorfismo -174GC do gene da IL â 6 foi tipificado pela tÃcnica de reaÃÃo em cadeia da polimerase (PCR), utilizando-se iniciadores de sequÃncia especÃfica (PCR-SSP) (One-Lambda). As medianas de concentraÃÃes sÃricas de IL-6 para os grupos ILTB, TB e saudÃveis foram de, respectivamente, 1,7 pg/mL, 4,3 pg/mL e 0,5 pg/mL (p < 0,0001). Nos trÃs grupos estudados, o genÃtipo encontrado com maior frequÃncia foi o G/G [ILTB = (80%); TB = (58,9%); saudÃveis = (62,8%)]. Em conclusÃo, podemos inferir que a IL-6 deve desempenhar um papel importante na manutenÃÃo do estado de latÃncia, haja vista que sua concentraÃÃo, nos indivÃduos com ILTB, foi 3,4 vezes maior que no grupo saudÃvel. Ademais, constatamos que, na populaÃÃo estudada, o polimorfismo -174GC nÃo se mostrou funcional no Ãmbito da infecÃÃo latente pelo Mycobacterium tuberculosis.<br>Interleukin-6 (IL-6) is an important cytokine involved in the pathogenesis of multiple infectious diseases. The aim of this study was to investigate the levels of IL-6 production and to correlate to the -174G>C polymorphism at the IL-6 gene in latent infection with M. tuberculosis (ILTB). As controls, two groups were used. One of them with active pulmonary tuberculosis (TB) patients and the other with healthy blood donors. ILTB group was composed by 15 individuals, selected among active pulmonary TB contacts seen at the Hospital SÃo Josà de DoenÃas Infecciosas and the Centro de SaÃde da FamÃlia AnastÃcio MagalhÃes. TB group had 38 patients with active pulmonary disease seen at the Hospital de Messejana, Hospital de Maracanaà and the Hospital Geral Dr. CÃsar Cals. The third group was composed by 63 healthy blood donors from the Centro de Hematologia e Hemoterapia do CearÃ. Serum levels of IL-6 were measured by an ELISA using specific kits from Invitrogen Corporation. For DNA purification a GFX Genomic Blood DNA Purification kit (GE Healthcare) was used. The -174GC polymorphism was analyzed by a SSP-PCR method using One-Lambda kits. Median values of serum levels of IL-6 from ILTB, TB and healthy groups were, respectively, 1.7 pg/mL, 4.3 pg/mL and 0.5 pg/mL (p < 0.0001). For the three studied group, the most frequent genotype found was the G/G (ILTB = 80%; TB = 58.9%; saudÃveis = 62.8%). In conclusion, it is possible to consider that IL-6 should play an important role in the maintenance of latent infection state as its concentrations were 3.4 fold higher in ILTB group than that of healthy controls. Moreover, the -174GC polymorpism was not functional in the ILTB group.
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Berg, Arjen van den. "Post-transcriptional modulation of IL-6 and IL-8 responses in structural airway cells." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2006. http://dare.uva.nl/document/32479.
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ARAÚJO, Maria da Conceição Melo. "Polimorfismo nos genes il-1 e il-6 e o insucesso de implantes dentários." UNIVERSIDADE FEDERAL DE PERNAMBUCO, 2014. https://repositorio.ufpe.br/handle/123456789/14987.
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Previous issue date: 2014-08-26<br>REUNI<br>Objetiva-se verificar, através de um estudo tipo série de casos, a associação do polimorfismo do gene IL-1β [região +3954(T\C)] e do gene IL-6 [região -174(G\C)] ao insucesso de implantes dentários. Noventa e quatro pacientes, de ambos os sexos, reabilitados com cento e noventa e quatro implantes dentários Straumann® (Waldenburg, Switzerland) foram avaliados clínica e radiograficamente para os seguintes parâmetros: mobilidade, queixas subjetivas persistentes, infecção peri-implantar recorrente com supuração, radiolucência contínua ao redor do implante, profundidade de sondagem ≥ 5mm e sangramento à sondagem. Se o implante apresentasse algum destes parâmetros, era considerado como insucesso ou falha e os que não apresentaram foram considerados como sucesso. Células da mucosa jugal foram coletadas para a análise do polimorfismo dos genes IL-1β e IL-6 através da reação em cadeia da polimerase pela técnica do comprimento do fragmento de restrição (PCR-RFLP). Dentre os implantes avaliados, 28,35% apresentaram insucesso. Não foi encontrada diferença estatisticamente significante entre o grupo de falha\insucesso dos implantes em relação ao genótipo dos genes IL-1β e IL-6. Dentro dos limites desta pesquisa, pode-se concluir que não existe associação entre o polimorfismo genético específico e falha do implante dentário em termos de complicações biológicas na população estudada. Estudos longitudinais adequadamente alimentados são necessários para fornecer mais informações.<br>To verify, through a case series study, the association of the polymorphism of the IL-1β gene [+3954 region (T \ C)] and the IL-6 gene [-174 region (G \ C)] to the failure of dental implants. Ninety-four patients of both genders, rehabilitated with one hundred ninety-four dental implants Straumann® (Waldenburg, Switzerland) were evaluated clinically and radiographically for the following parameters: mobility, persistent subjective complaints, recurrent peri-implant infection with suppuration, the continuous radiolucent around the implant, probing depth ≥ 5 mm and bleeding on probing. If the implant submit any of the parameters was considered as failures or crashes, and those who had not were considered successful. Cells from the oral mucosa for analysis of polymorphism of IL-1β and IL-6 genes by polymerase chain reaction technique for the length of the restriction fragment was collected (PCR-RFLP). Among the implants reviews, 28,35% were unsuccessful. No statistically significant difference was found between the failure group \ failure of implants in relation to the genotype of IL-1β and IL-6 genes. Within the limits of this research, it can be concluded that there is no association between specific genetic polymorphisms and dental implant failure in terms of biological complications in this population. Adequately powered longitudinal studies are needed to provide more information.
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Klebow, Sabrina [Verfasser]. "The role of theproinflammatory cytokines IL-17, IL-6 and IL-1 in (IMQ-induced) psoriasis / Sabrina Klebow." Mainz : Universitätsbibliothek Mainz, 2016. http://d-nb.info/1111809518/34.
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Palmer, Jodie. "The IL-6 type cytokine family in prostate cancer." Monash University, Centre for Functional Genomics and Human Disease, 2003. http://arrow.monash.edu.au/hdl/1959.1/9441.
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Ayala-Fontanez, Nilmarie. "Paradoxical onset of psoriasis after IL-6 receptor blockade." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1436396399.
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Schebesta, Kathrin [Verfasser]. "Das Endothel sezerniert Interleukin-6 (IL-6) und stimuliert die adrenale Interleukin-6 und Aldosteronsynthese über einen Interleukin-6 unabhängigen Mechanismus / Kathrin Schebesta." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2015. http://d-nb.info/1079652612/34.
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Peron, Jean Pierre Schatzmann. "O fenômeno da tolerância oral e a regulação de células patogênicas Th17 no modelo de encefalomielite experimental auto-imune." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-17092008-113606/.
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Recentemente demonstrou-se o papel de células T produtoras de IL-17 na patogênese da esclerosa múltipla e de seu modelo, a EAE. Através da produção desta e de outras citocinas, a população chamada Th17 promove o rompimento da barreira hematoencefálica e a conseqüente infiltração de células patogênicas para dentro do SNC. Nesse contexto, em nosso trabalho utilizamos o fenômeno da tolerância oral para avaliar a capacidade deste em suprimir a resposta imune durante o modelo de EAE, mais especificamente as células Th17. Nossos dados demonstram uma diminuição de IL-17 tanto na periferia como no SNC dos animais tolerados. Além disso, detectamos menos CCL2 e IL-6 em células extraídas do CNS dia 10 pós-imunização. Não observarmos diferença na produção de IL-4,5,10, 13, IL-12p70, TNF-<font face=\"symbol\">a, e IFN-<font face=\"symbol\">g entre os grupos. Em suma, nossos resultados mostram que o fenômeno da tolerância oral é capaz de suprimir parâmetros de EAE devido a uma menor capacidade linfoproliferativa associada a uma supressão de células patogênicas Th17 tanto na periferia como no SNC.<br>It has recently been shown the role of IL-17 secreting cells on the pathogenesis of multiple sclerosis and also in its model, EAE. Due to the secretion of this and other cytokines, the population so called Th17, promotes the disruption of the blood-brain barrier and the following infiltration of pathogenic cells into the CNS. In this context, in our work we used the oral tolerance phenomenon to evaluate its supressive capacity, more specifically over the Th17 cells. We showed that oral tolerated mice has a diminished production of IL-17 both in the periphery and in the CNS. Futhermore, we detected lower levels of CCL2 and IL-6 also from brain and spinal cord extracted mononucear cells at day 10th post-immunization. We were not able to detect differences on IL-4,5,10, 13, IL-12p70, TNF-<font face=\"symbol\">a, e IFN-<font face=\"symbol\">g between the groups. Thus, our results show that the oral tolerance phenomenon suppresses EAE findings, mainly due to a lower lymphoprolipherative response associated to a supression over the expansion of Th17 pathogenic T cells both in the periphery and inside the CNS.
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Loung, Le Anh. "Genetic variations in the interleukin-6(IL-6) gene : implication in coronary heart disease (CHD)." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406589.
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Vilela, Josie Fadul 1982. "Investigação dos polimorfismos dos genes da interleucina-1 (IL-1), IL1RN, IL-4, IL-6 e IL-10 em pacientes adultos portadores de púrpura trombocitopênica imune = Investigation of interleukin-1 (IL-1), IL1RN, IL-4, IL-6 and IL-10 gene polymorphism adult patients with immune thrombocytopenic purpura." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310653.
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Orientador: Marcelo Addas Carvalho<br>Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas<br>Made available in DSpace on 2018-08-21T03:08:54Z (GMT). No. of bitstreams: 1
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Previous issue date: 2012<br>Resumo: A Púrpura Trombocitopênica Imune (PTI) é uma doença autoimune caracterizada pela presença de autoanticorpos contra as glicoproteínas de membrana plaquetária, tais como GPIIb/IIIa e GPIb/IX. O processo patogênico da PTI envolve uma destruição acelerada das plaquetas pelo sistema retículo-endotelial e a presença de sangramentos mucocutâneos. A reação inflamatória em doenças infecciosas e autoimune é regulada por um balanço entre as citocinas pró e anti-inflamatórias e a PTI tem sido associada com a desregulação das respostas e atividades de citocinas. Uma associação entre os polimorfismos de genes de citocinas que afetam sua produção e secreção foram relatadas em doenças infecciosas, alérgicas, autoimunes, e malignas, tanto na fase de formação quanto no decurso da doença e nas suas respostas ao tratamento. Neste estudo, o objetivo foi avaliar a importância dos polimorfismos IL1B -511C/T, IL1B +3953C/T, IL1RN intron 2 VNTR, IL4 -590C/T, IL4 intron 3 VNTR, IL6 -174G/C, IL10 -1082G/A, IL10 -819C/T e IL10 -592 A/C em pacientes portadores de PTI na região de Campinas, SP e investigar a associação entre os genótipos identificados e a resposta clínica do paciente ao tratamento. Utilizamos o método PCR e digestão com enzima de restrição (PCR-RFLP) ou PCR em Tempo real (RT-PCR) para identificação dos polimorfismos. No total, 216 pacientes adultos diagnosticados com PTI foram pareados com 119 controles saudáveis constituídos por doadores voluntários do Centro de Hematologia e Hemoterapia da UNICAMP. Os dados clínicos como contagem de plaquetas ao diagnóstico, tipo de tratamento e resposta, foram obtidos através dos prontuários médicos. A análise de frequências dos alelos e genótipos dos polimorfismos IL1B - 511C/T, IL1B +3953C/T, IL6 -174G/C, IL10-1082G/A, IL10 -819C/T e IL10 -592A/C de pacientes portadores de PTI comparadas ao grupo controle não mostrou diferenças significativas entre os dois grupos. No entanto, para os polimorfismos IL1RN intron 2 VNTR, IL4 -590C/T, IL4 intron 3 VNTR e para os haplótipos de IL10 houve uma diferença significativa ao compararmos as frequências polimórficas entre os dois grupos. Analisando-se os polimorfismos associados com parâmetros clínicos, este estudo mostrou que o genótipo IL1B -511CC estava mais presente em indivíduos com boa resposta à esplenectomia. Pode-se concluir que o estudo de características genéticas dos pacientes portadores de PTI na região de Campinas, SP pode ajudar a esclarecer o perfil de pacientes acometidos pela doença nesta região, identificando grupos de maior risco e a entender qual polimorfismo pode estar associado a uma melhor resposta clínica, projetando uma nova linha de investigação<br>Abstract: The immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by the presence of autoantibodies against the platelet membrane glycoproteins such as GPIIb/IIIa and GPIb/IX. The pathogenic process of ITP involves an accelerated destruction of platelets by reticuloendothelial system and the presence of mucocutaneous bleeding. The inflammatory reaction in infectious and autoimmune diseases is regulated by a balance between pro and anti-inflammatory cytokines and ITP has been associated with dysregulation of cytokine responses and activities. An association between cytokine gene polymorphisms that affect their production and secretion have been reported in infectious, allergic, autoimmune, and malignant diseases, both during training and during the illness and its response to treatment. The aim of this study was to evaluate the importance of IL1B -511C/T, IL1B +3953 C/T, IL1RN intron 2 VNTR, IL4 -590C/T IL4 intron 3 VNTR, IL6 -174G/C, IL10 -1082G/A, IL10 -819C/T and IL10 -592A/C polymorphisms in patients with ITP in the region of Campinas, SP, and investigate the association between different genotypes and clinical responses to treatment. We used the PCR method and digestion with restriction enzyme (PCR-RFLP) or real-time PCR (RT-PCR) to identify polymorphisms. In total, 216 adult patients diagnosed with ITP were matched with 118 healthy controls. The clinical data such as platelet count at diagnosis, type of treatment and response were obtained from medical records. Analysis of allele and genotypes frequencies of IL1B -511C/T, IL1B +3953C/T, IL6 -174G/C, IL10 - 1082G/A, IL10 -819C/T and IL10 -592A/C polymorphisms in patients with ITP compared to the control group showed no significant differences between the two groups. However, for IL1RN intron 2 VNTR polymorphisms, IL4 -590C/T, IL4 intron 3 VNTR and IL10 haplotypes there were a significant difference when comparing polymorphic frequencies between the two groups. Analyzing the polymorphisms associated with clinical parameters, this study showed that IL1B -511CC genotype was more frequent in individuals with good response to splenectomy. It can be concluded that the study of genetic characteristics of patients with ITP in the region of Campinas, SP should help clarify the profile of patients affected, identifying groups at higher risk and understanding which polymorphism may be associated with better clinical response<br>Mestrado<br>Clinica Medica<br>Mestra em Clínica Médica
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Gil, Ibánez Inés [Verfasser], and Henning [Akademischer Betreuer] Wege. "Ligand-independent IL-6 pathway activation (L-gp130) accelerates the transformation of proliferating human hepatocytes via increased oxidative stress in comparison to ligand-dependent IL-6 pathway activation (Hyper-IL-6) / Inés Gil Ibánez. Betreuer: Henning Wege." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2015. http://d-nb.info/1079655220/34.
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Shive, Carey Lynn. "The impact of inflammatory cytokines, il-6 and il-1beta, on the pathogenesis of immune failure in HIV disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1396627515.
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DESIATO, GENNI. "Regulation of the GABA switch by immunomodulatory signals." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2018. http://hdl.handle.net/10281/199045.
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L'acido Gamma Amino butirrico, noto come GABA, rappresenta il principale neurotrasmettitore inibitorio del Sistema Nervoso nell'individuo adulto. Tuttavia, durante le precoci fasi di sviluppo, il GABA ha attività depolarizzante ed eccitatoria, fondamentale per il successivo e corretto sviluppo della rete. Il "GABA switch" rappresenta quindi un evento critico dello sviluppo neuronale, caratterizzato da uno shift funzionale della trasmissione GABAergica, da eccitatoria a inibitoria, le cui alterazioni sono comuni caratteristiche dei disordini del neurosviluppo, solitamente associati a disabilità cognitive e deficit comportamentali.
Anche se i meccanismi molecolari del switch del GABA sono stati ampiamente descritti, nuovi regolatori di questo evento sono continuamente individuati e caratterizzati.
È noto che le Cellule Staminali Mesenchimali (MSC) rappresentano buoni candidati a fini terapeutici, data la loro influenza positiva nella neuroprotezione verso le malattie neurologiche e immuno-mediate. Tuttavia, sempre più crescenti evidenze stanno dimostrando che le vescicole extracellulari (EVs) derivate da MSCs potrebbero rappresentare delle candidate migliori rispetto all'utilizzo di cellule per possibili applicazioni cliniche, mostrando un miglior profilo di sicurezza e utilizzo, e minori effetti collaterali.
Tra le molecole immunomodulatorie, notevoli studi considerano l'Interleuchina 6 (IL-6) come un nuovo fattore neurotrofico, nonostante il suo ruolo ben descritto nelle malattie dello sviluppo neurologico, come l'autismo.
Combinando tecniche funzionali (imaging di calcio e cloro) e approcci molecolari (RT-PCR), abbiamo osservato che le MSC-EVs, ma non le MSCs promuovono il GABA switch e aumentano l'espressione dei marcatori sinaptici inibitori del GABA. Allo stesso modo, l'esposizione precoce di IL-6 nei neuroni ippocampali, accelera il GABA switch modulando la trasmissione GABAergica e sovraregolando l'espressione di KCC2, in modo STAT-3- dipendente.
Studi in letteratura suggeriscono la presenza di citochine come IL-6 all'interno delle MSC-MVs, ed è per questo possibile speculare sull'azione sinergica di questi due fattori, se combinati insieme. ILe evidenze osservate in questo lavoro aprono la possibilità di sfruttare tale sistema come nuovo approccio terapeutico, per veicolare molecule immunomodulanti tramite organelli sicuri e non tossici, in quelle condizioni patologiche caratterizzate da un ritardato GABA switch, come nel caso dei disordini dello neurosviluppo.<br>The neuronal “GABAergic switch” represents a critical event that occurs early in life before birth, during brain development, characterized by the excitatory-to-inhibitory transition of the GABAergic transmission. Impairments in the accomplishment of this event have been associated to a remarkable excitation/inhibition network imbalance, usually linked to cognitive disabilities and behavioural deficits, typical hallmarks of neurodevelopmental disorders.
Even though molecular mechanisms of the GABA switch have been widely described, novel regulators of this event are being continuously characterized.
It is well known that mesenchymal stem cells (MSCs) represent good candidates for therapeutic interventions, given their positive roles in neuroprotection against immune-mediated and neurological diseases. However, raising evidences are considering MSC-derived extracellular vesicles (EVs) better candidates than the whole cells for clinical applications, bearing more safety and less side effects.
Among the immunomodulatory molecules, increasing studies consider the cytokine Interleukin 6 (IL-6) as a novel trophic factor, despite its well described role in neurodevelopmental diseases, such as autism.
By taking advantage of a combination of functional (calcium and chloride imaging) and molecular approaches (RT-PCRs), we found that MSC-EVs but not MSCs accelerated the timing of the GABA switch and boosted the expression of the GABA inhibitory synaptic markers. Likewise, IL-6 early exposure in neurons accelerated the timing of the GABA switch by enhancing the GABAergic transmission and upregulating the expression of KCC2, in a STAT3- dependent manner.
Given several evidences suggesting the presence of IL-6 within the MSC-MV cargo it is possible to speculate about their synergistic action when combined. All these data open the possibility to harness such system as a new therapeutical approach, for delivering safe and nontoxic organelles to those pathological conditions characterized by a delayed GABA switch, such as neurodevelopmental disorders.
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Pereira, Daniele Sirineu. "Efeito do polimorfismo -174 G/C da região promotora do gene IL-6, índices plasmáticos de IL-6 e força muscular de mulheres idosas." Universidade Federal de Minas Gerais, 2008. http://hdl.handle.net/1843/MSMR-7WYHM5.
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The present study investigates the effect of -174 G/C promoter polymorphism of the interleukin-6 (IL-6) gene on the plasmatic levels of IL-6 and muscular strength, as well as the association between doses of IL-6 and the muscular strength of elderly women. The sample consisted of 199 institutionalized and community-living elderly patients (73.0 ± 7.8 years) in the city of Belo Horizonte, Brazil. The -174 G/C polymorphism in the promoter of the human IL-6 gene was determined by direct sequencing of a polymerase chain reaction product. The plasmatic concentrations of IL-6 were measured using the ELISA method. The muscular strength of the articulation of the knee was assessed using the Biodex System 3 Pro® isokinetic dynamometer. The covariance analysis (ANCOVA) was applied to investigate the effect of the polymorphism on the IL-6 levels and muscular strength, while the Pearson correlation index was used to assess the relation between the plasmatic levels of IL-6 and muscular strength. The -174 G/C promoter polymorphism affected the plasmatic levels of IL-6 in elderly women (p<0.01) due to the fact that the homozygotes for the G allele presented high levels of IL-6 (GG 3.85 pg/ml; GC+CC 2.13 pg/ml). This polymorphism did not directly influence the muscular strength of the elderly patients (p>0.05). No association was found between the plasmatic levels of IL-6 and the muscular strength of the knee extensors (r=0.087; p=0.306) and knee flexors (r=-0.011; p=0.894). The results of this study support previous reports which defend that the -174 G/C promoter polymorphism contributed to the individual variability of the IL-6 plasmatic levels in elderly women. This polymorphism did not influence the muscular strength of the elderly patients.<br>O presente estudo investigou o efeito do polimorfismo de nucleotídeo único -174G/C da região promotora do gene da IL-6 sobre os índices plasmáticos de IL-6 e a força muscular e, ainda, a associação entre dosagens de IL-6 e a força muscular em mulheres idosas. A amostra foi composta por 199 idosas entre institucionalizadas e da comunidade (73,0 ± 7,8 anos) na cidade de Belo Horizonte, Brasil. O polimorfismo -174G/C foi determinado por seqüenciamento direto de produto da reação em cadeia da polimerase. As concentrações plasmáticas de IL-6 foram mensuradas pelo método ELISA. A força dos músculos da articulação do joelho foi avaliada pelo dinamômetro isocinético Biodex System 3 Pro®. Análise de covariância (ANCOVA) foi usada para investigar o efeito do polimorfismo sobre os índices de IL-6 e força muscular, e o índice de correlação de Pearson para avaliar a relação entre os índices plasmáticos de IL-6 e a força muscular. O polimorfismo -174G/C afetou os índices plasmáticos de IL-6 em mulheres idosas (p<0,01), uma vez que homozigotas para o alelo G apresentaram índices de IL-6 superiores (GG 3,85 pg/ml, GC+CC 2,13 pg/ml). Não houve influência do polimorfismo sobre a força muscular das idosas (p>0,05). Nenhuma associação foi encontrada entre os índices plasmáticos de IL-6 e a força muscular de extensores (r=0,087; p=0,306) e flexores de joelho (r=-0,011; p=0,894). Os resultados deste estudo dão suporte às evidências de que o polimorfismo -174G/C do gene da IL-6 contribui para a variabilidade individual dos índices plasmáticos da IL-6 em mulheres idosas. O polimorfismo não influenciou a força muscular das idosas avaliadas.
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Ferrer, Villahoz Beatriz. "Influencia de la citoquina Interleuquina 6 (IL-6) adipocitaria y muscular en el control del metabolismo." Doctoral thesis, Universitat Autònoma de Barcelona, 2013. http://hdl.handle.net/10803/116320.
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La interleuquina -6 (IL-6) es una citoquina pleiotrópica cuya función principal se da en el sistema inmune en el control de la inflamación. Realiza importantes funciones en la homeostasis del sistema nervioso central (SNC), en la respuesta al ejercicio físico e incluso en el metabolismo (particularmente en funciones relacionadas con la insulina). Diversos estudios han demostrado que la IL-6 podría tener un papel en el control del peso corporal tanto a nivel de SNC como periférico, aunque no está claro si la IL-6 endógena que participa en la regulación del peso corporal a nivel del SNC procede del mismo SNC o bien de la periferia. La IL-6 secretada por tejidos periféricos no inmunológicos podría tener un papel importante y esto es actualmente motivo de debate.
En la última década se ha puesto de relevancia la capacidad del músculo esquelético de secretar mioquinas. La IL-6 es la principal mioquina producida y liberada durante la contracción muscular por lo que se ha postulado que podría ser un factor que media los efectos del ejercicio a nivel metabólico. El tejido adiposo también la produce y secreta siendo la principal fuente de IL-6 en situaciones no inflamatorias.
Dado el importante papel que juegan el músculo esquelético y el tejido adiposo en el control del metabolismo y que ambos son los principales órganos secretores de IL-6 en situaciones no inflamatorias, decidimos estudiar el papel de de la IL-6 producida por estos tejidos en el metabolismo y en el control del peso corporal. Para ello desarrollamos dos modelos de knock-out condicionales para la IL-6: uno en el músculo esquelético y el otro en el tejido adiposo. Estos animales se han caracterizado en condiciones basales y en respuesta a una dieta en grasas. Se hizo el seguimiento del peso y de la ingesta, se estudió la respuesta a la glucosa y a la insulina y se analizó el peso de diferentes tejidos, los niveles varios metabolitos y hormonas y la expresión de algunos genes implicados en el metabolismo y en la inflamación. Los datos obtenidos muestran que la deficiencia de IL-6 tanto muscular como adipocitaria tiene efectos dependientes del sexo. No se observaron alteraciones en el crecimiento en ninguno de los modelos pero sí diferencias en la ganancia de peso. Los machos deficientes en IL-6 muscular engordaron menos que sus controles y en el caso de las hembras se observó lo contrario. Estas diferencias se exacerbaron en los animales alimentados con la dieta grasa. Por lo que respecta a la deficiencia de IL-6 adipocitaria los efectos en la ganancia de peso sólo se vieron en los ratones alimentados con dieta grasa en donde la deficiencia de IL-6 sólo mostró efecto significativo en las hembras que ganaron menos peso que las controles. El estudio de la ingesta y de los neuropéptidos hipotalámicos que controlan la ingesta y el gasto energético sugiere que los efectos de la IL-6 se darían sobretodo en el control del gasto energético y no tanto por cambios en la ingesta. Así, en condiciones basales los machos deficientes en IL-6 muscular presentaron un perfil de activación del gasto energético y en las hembras lo contrario. Por lo que se refiere a la deficiencia de IL-6 adipocitaria, aunque no hubo diferencias en el peso, sí las hubo en los neuropéptidos hipotalámicos.
En resumen, la IL-6 tiene efectos en el control de la homeostasis energética a nivel central y periférico. La disminución de los niveles plasmáticos de IL-6, según su origen, tiene diferentes efectos a nivel local regulando la expresión de otro u otros factores que probablemente sea o sean los responsables de los efectos observados.<br>Interleukine 6 is a pleiotropic cytokine whose main function is regulating inflammation in the immune system. However, IL-6 also affects the central nervous system (CNS), and it participates in the exercise response and in metabolism (mainly insulin-related functions). Several studies show that IL-6 could have a role in the control of body weight in both the CNS and the periphery. It is unknown, and currently the matter of debate, whether CNS-acting IL-6 is produced in situ or elsewhere. It would then be possible that IL-6 produced by non-immunologic tissues had an important role in the control of body weight.
In the last few decades, it has been shown that skeletal muscle produces and secretes myokines. IL-6 is the most abundant and it is produced during muscular contraction, possibly participating in some of the exercise-induced metabolic changes. Adipose tissue also produces and secretes this cytokine and it is the main source of IL-6 in non-inflammatory conditions.
Skeletal muscle and adipose tissue play an important role in metabolism. These tissues are also the main source of IL-6 in non-inflammatory conditions. That is why we decided to investigate the metabolic role of IL-6 produced by these tissues and its actions in the control of body weight. We generated two different IL-6 conditional knock-outs: one in the skeletal muscle and the other in the adipose tissue. These animals were characterized in basal conditions and after being fed a high fat diet. Body weight and food intake were measured. Glucose and insulin response were studied. Several tissues were weighted. Some metabolites and hormones levels and metabolic and inflammatory gene expression were also analyzed. In both models IL-6 deficiency had a sex-dependent effect. Our data suggest that these mice had a normal growth. However, there were changes in body weight gain. Muscular IL-6 deficient mice gained less weight than controls, whereas in females the opposite occurred. These differences were exacerbated in mice fed a high fat diet. Regarding the adipose IL-6 deficiency model, adipose IL-6 deficiency only had an effect in body weight in mice fed a high fat diet. Thus, knockout females showed resistance to obesity, gaining less weight than controls. In males this effect was smaller and not significant. Food intake and hypothalamic neuropeptides controlling food intake and energy expenditure were analyzed, too. Our data suggest that body weight changes would be mainly caused by changes in energy expenditure rather than by changes in food intake. Thus, in basal conditions muscular IL-6 deficient males showed energy expenditure activation and in females the opposite occurred. In the case of adipose IL-6 deficiency, although body weight gain in basal conditions was unchanged, hypothalamic neuropeptide expression was altered.
In conclusion, IL-6 has either central or peripheral effects on the control of energy homeostasis. Decreased levels of IL-6 have, depending on their origin, different local effects in the regulation of other factors that probably caused the observed changes.
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Yan, Jin, Ohannes Melemedjian, Theodore Price, and Gregory Dussor. "Sensitization of dural afferents underlies migraine-related behavior following meningeal application of interleukin-6 (IL-6)." BioMed Central, 2012. http://hdl.handle.net/10150/610216.
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BACKGROUND:Migraine headache is one of the most common neurological disorders, but the pathophysiology contributing to migraine is poorly understood. Intracranial interleukin-6 (IL-6) levels have been shown to be elevated during migraine attacks, suggesting that this cytokine may facilitate pain signaling from the meninges and contribute to the development of headache.METHODS:Cutaneous allodynia was measured in rats following stimulation of the dura with IL-6 alone or in combination with the MEK inhibitor, U0126. The number of action potentials and latency to the first action potential peak in response to a ramp current stimulus as well as current threshold were measured in retrogradely-labeled dural afferents using patch-clamp electrophysiology. These recordings were performed in the presence of IL-6 alone or in combination with U0126. Association between ERK1 and Nav1.7 following IL-6 treatment was also measured by co-immunoprecipitation.RESULTS:Here we report that in awake animals, direct application of IL-6 to the dura produced dose-dependent facial and hindpaw allodynia. The MEK inhibitor U0126 blocked IL-6-induced allodynia indicating that IL-6 produced this behavioral effect through the MAP kinase pathway. In trigeminal neurons retrogradely labeled from the dura, IL-6 application decreased the current threshold for action potential firing. In response to a ramp current stimulus, cells treated with IL-6 showed an increase in the numbers of action potentials and a decrease in latency to the first spike, an effect consistent with phosphorylation of the sodium channel Nav1.7. Pretreatment with U0126 reversed hyperexcitability following IL-6 treatment. Moreover, co-immunoprecipitation experiments demonstrated an increased association between ERK1 and Nav1.7 following IL-6 treatment.CONCLUSIONS:Our results indicate that IL-6 enhances the excitability of dural afferents likely via ERK-mediated modulation of Nav1.7 and these responses contribute to migraine-related pain behavior in vivo. These data provide a cellular mechanism by which IL-6 in the meninges causes sensitization of dural afferents therefore contributing to the pathogenesis of migraine headache.
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Shakya, Astha. "ERK3 negatively regulates the IL-6/STAT3 signaling via SOCS3." Wright State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=wright1576834819053154.
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Lin, Wai Wai. "TRAF3 regulates B cell survival and IL-6 receptor signaling." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1678.
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Tumor-necrosis factor (TNF)-receptor (R) associated factor 3 (TRAF3) is an important adaptor protein that plays a variety of context-dependent regulatory roles in all types of immune cells. In B cells, TRAF3 mediates signaling downstream of CD40, B cell activating factor (BAFF)-R, and toll-like receptors (TLR)s to restrain B cell survival and function. Downstream of CD40 and BAFF-R, TRAF3 negatively regulates NF-κB2 activation through NF-κB inducing kinase (NIK) stabilization. NF-κB2 activation is important for B cell-homeostatic survival. However, the constitutively active NF-κB2 in other TRAF3 deficient immune cell types does not lead to increased cell survival. More importantly, loss-of-function mutations of the TRAF3 gene are found at relatively high frequencies in B cell malignancies such as multiple myeloma and B cell lymphoma. Therefore, TRAF3 plays a critical and unique role in B cells to restrain cell survival and differentiation that contributes to B cell malignancies. In this study, we aim to identify TRAF3 modulated survival pathways that contribute to homeostatic B-cell survival and B-cell differentiation.
We found that TRAF3 degradation was not sufficient or necessary to induce NF-κB2 activation. We also showed that TRAF3 degradation is dependent on association with TRAF2 and cytoplasmic tail of CD40 or BAFF-R. TRAF3 regulation of NIK is important for mature B cell development; however, NIK only partially contributes to TRAF3-mediated B cell survival. TRAF3 also regulates the protein level of proviral integrations of Moloney virus (Pim2), a pro-survival serine/threonine protein kinase encoded by the Pim2 gene, to restrain B cell survival; this regulation can operate independently of the NF-κB2 pathway. Furthermore, we showed that TRAF3 negatively regulates IL-6R signaling, a pathway that contributes to expansion of the plasma cell compartment and to the pathogenesis of multiple myeloma, a plasma cell malignancy. We found that TRAF3 facilitates recruitment of PTPN22, a tyrosine phosphatase, to associate with Jak1 following IL-6 binding to the IL-6R complex. This regulation by TRAF3 restrains plasma cell differentiation, and also provides the first demonstration that PTPN22 regulates cytokine receptor signaling.
Collectively, these findings highlight the importance of TRAF3 in the regulation of B cell-specific survival and differentiation pathways. This information could be exploited for more precise and effective therapeutic choices in treatment of B cell malignancies with TRAF3 deficiencies.
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Kurth, Ingo. "Untersuchungen zur Zytokinbindung und Rezeptoraktivierung des Signaltransduktors gp130 durch seine Liganden IL-6 und IL-11." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=968740758.
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Gallion-Rochette, Emmanuelle. "Adaptations cellulaires et moléculaires de la réponse inflammatoire à l'activité physique chez les enfants atteints d'arthrite juvénile idiopathique." Thesis, Université Clermont Auvergne (2017-2020), 2018. http://www.theses.fr/2018CLFAC030.
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L'arthrite juvénile idiopathique (AJI) est une maladie rare chronique caractérisée par une inflammation persistante qui se manifeste par des douleurs articulaires, le gonflement des articulations et la limitation des mouvements articulaires. La fatigue et les douleurs entraînent une diminution de l'activité physique et une sédentarité accrue. Ce manque d'activité physique a pour conséquence une altération de la qualité de vie et une aggravation de la fatigue chronique, des troubles de l'humeur et des troubles métaboliques chez ces enfants. Les études sur les programmes d'exercices physiques montrent que l'exercice physique est bénéfique pour cette population. Mais les mécanismes d’action permettant de comprendre comment elle améliore la qualité de vie et la santé de l'enfant atteint d'arthrite juvénile idiopathique sont encore mal connus. Notre objectif était d’explorer la réponse physiologique à l’exercice des enfants et adolescents atteints d’arthrites juvéniles idiopathiques. Nous nous sommes intéressés principalement au métabolisme énergétique à l’exercice et à la fonction musculaire chez ces enfants. Nous avons étudié l’impact de la pathologie, des traitements par anti-TNF-α et de l’activité de la maladie sur ce métabolisme. Ensuite, nous avons étudié la sécrétion induite par l’exercice des myokines telles que l’IL-6 et les calgranulines en post exercice immédiat et dans les 24h suivant l’exercice<br>Juvenile idiopathic arthritis (JIA) is a rare chronic inflammatory disease characterized by persistent inflammation that is manifested by joint pain, swelling of the joints and limitation of range of motion. Fatigue and pain are the most frequent complaints in patients with JIA, lead to a decline in physical activity and a sedentary lifestyle of these children. This lack of physical activity results in impaired quality of life and worsening of chronic fatigue, mood disorders and metabolic disorders in these children. Studies of exercise programs show that exercise is beneficial for this population. But the mechanisms of action to understand how it improves the quality of life and health of children with juvenile idiopathic arthritis are still poorly understood. Our aim was to explore the physiological response to exercise in children and adolescents with juvenile idiopathic arthritis. We focused primarily on energy metabolism to exercise and muscle function in these children. We looked at the impact of the pathology, anti-TNF-α treatments and the activity of the disease on this metabolism. Next, we adressed the exercise-induced secretion of myokines such as IL-6 and calgranulins in immediate post exercise and within 24 hours after exercise
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Guillot, Xavier. "Effets thérapeutiques et anti-inflammatoires de la cryothérapie dans les rhumatismes inflammatoires." Thesis, Besançon, 2016. http://www.theses.fr/2016BESA3009/document.
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La cryothérapie est utilisée de manière large et empirique à visée adjuvante dans les rhumatismes inflammatoires, avec un niveau de preuve faible. Dans une revue systématique de la littérature, en poolant les données de 6 études non contrôlées, nous avons pu démontrer que la cryothérapie (locale ou corps entier) appliquée deux fois par jour pendant 7 à 15 jours réduisait significativement l'EVA douleur et le score d'activité DAS25 dans la polyarthrite rhumatoïde. La cryothérapie locale (glace ou gaz froide) montrait par ailleurs des effets taille intra-classes supérieurs à ceux obtenus en utilisant la cryothérapie corps entier. L'objectif de ce travail était de mesurer les effets de la cryothérapie locale sur al douleur, l'inflammation synoviale et systémique chez les patients arthritiques et dans le modèle murin d'arthrite à l'adjuvant. Dans les études randomisées CDRI et ALGGAR, nous avons évalué les effets de deux applications locales de froid (glace versus gaz froid) sur la douleur, l'activité Doppler et les taux protéiques de cytokines intra-articulaires controlatéraux non souffrant d'arthrites de genou non septiques. Les genoux arthritiques controlatéraux non traités étaient utilisés comme contrôles. Nous avons par ailleurs étudié in vitro les effets de l'hypothermie modérée (30°C pendant 2heures) sur l'expression protéique des cytokines dans un modèle de culture de rotules de rats arthritiques. Nous avons enfin étudié in vitro dans l'arthrite à l'adjuvant les effets de l'application sub-chronique de glace ou de gaz froid (2 fois par jour pendant 14 jours versus contrôles arthritiques non traités) sur le score d'arthrite, le diamètre de cheville, la transcription des gènes codant pour les cytokines pro-inflammatoires dans les pattes arrières (Q-RT-PCR) et l'expression protéique des cytokines dans le plasma (Multiplex et ELISA) après 14 jours de traitement. Dans l'étude CDRI, la cryothérapie locale (glace et gaz froid) réduisait significativement l'EVA douleur ainsi que le score Doppler dans les genoux traités, ces effets persistant le lendemain des deux applications. Dans une analyse intermédiaire des résultats de l'étude ALGGAR, en combinant les deux groupes de traitement (glace et gaz de froid), nous avons observé une baisse des taux d'IL-6, d'IL-1β et de VEGF dans le liquide articulaire arès deux applications. dans les cultures d'explants de rotules de rats arthritiques, l'hypothermie ponctuelle réduisait significativement les taux d'IL-6, IL-17A et IL-1β dans les pattes arrières après 14 jours de traitement. Les deux modalités réduisaient significativement les niveaux plasmatiques d'IL-17A et la glace réduisait en outre les taux d'IL-6 et de VEGF. Nous n'avons observé aucun effet de la cryothérapie locale sur le voie du TNF-α chez l'homme ni chez l'animal. Nos résultats démontrent pour la première fois un effet thérapeutique et anti-inflammatoire de la cryothérapie locale dans l'arthrite. Les effets biologiques était IL-6/IL-147 dépendants et TNF-α indépendants. Des études complémentaires permettront de mieux caractériser les mécanismes moléculaires sous-jacents et de déterminer su la cryothérapie locale pourrait être une alternative aux AINS et corticoïdes dans les rhumatismes inflammatoires<br>Cryotheapy i widely and empirically used in an adjuvant setting in inflammatory rheumatic diseases, with a low level of evidence. We performed a systematic review of the literature and, by pooling data from 6 non-controlled studies, we could show that local cryotherapy (local or whole-body cryotherapy) applaied twice a day for 7-15 days significantly reduced the pain VAS and the DAS28 activity score in rheumatoid arthritis. Furthermore, local cryotherapy (ice packs or cold gas) showed significantly greater intra)class effect-sizes compared to whole-body cryotherapy. The aim of this work was to measure the effects of local cryotherapy on pain, synovial and systemic inflammation in arthrici patients and in the murine model of adjuvant-induced arthritis. First, in the CDRI and ALGGAR randomized studies, we evaluated the effects of 2 local cold applications (ice versus cold gas) on pain, power Doppler activity and intra-joint cytokine protein levels in 46 patients suffering from non-septic knee arthritides. Contralateral arthritic knee were used as control. Secondly, we studied the in vitro effects of mild hypothermia (30°C for 2 hours) on cytokine protein expression in a model of cultured arthritic rat patellae. Thidly, we studied the in vitro effects of sub-chronically applied ice or cold gas (twice a day for 14 days versus non-treated arthritic controls) on the arthritis score, the ankle diameter, pro-inflammatory cytokine gene transcription levelsin hind paws (Q-RT-PCR) and cytokine plasma protein levelx (Multiplex and ELISA) after 14 days of treatment. In the CDRI study, local cryotherapy (ice and cold gas) significantly reduced the pain VAS and the power Doppler score in treated kness, and these effects remained significant the day afetr 2 cold applicaitions. In an intermediate analysis of the ALGGAR study results, by pooling the 2 treatment groups, we could show significant decreases in IL-6 protein, IL-1β and VEGF synovial fluid protein levels after 2 cold applicatios. In arthritic rat patella explangt culture experiments, punctual hypothermia significantly reduced IL-6 protein levels. In vivon ice was more efficient on the clinical parameters and better tolerated compared to cold gas. Both techniques significantly reduced IL-6, IL-17A ans IL-1β gene transcription levels in hind paws after 14 days of treatment. Both techniques redcued IL-17A plasma protein levles, while ice also reduced IL-6 and VEGF plasma protein levels. Conversely, we observed no effect of local cryotherapy on the TNF-α pathway, neither in patients nor in our animal model. Here we demonstrate for the first time therapeutic and anti-inflammatory effet-cts of local cryothepary in arthritis. The biological effects were IL-6/IL-17-driven and TNF-α independent. Further studies will help elucidate the underlying molecular mlechanisms involved and detemrine whether local cryotherapy might be a safer alternative to NSAIDs ans corticosteroids in inflammatory rheumatic diseases
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DiLorenzo, Frank Michael. "The Effects of Dha Supplementation on Markers of Inflammation and Muscle Damage Following an Acute Eccentric Exercise Bout." Thesis, Virginia Tech, 2012. http://hdl.handle.net/10919/43760.
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Aim: The purpose of this study was to investigate the influence of docosahexaenoic acid (DHA) on muscle damage and inflammation following an acute eccentric exercise bout. Methods: A double-blind placebo-controlled, study was performed using 41 healthy, untrained males aged 18-28 y who consumed either 2 g/d DHA or placebo (PL, corn oil) for 32 days. Supplements were consumed for 28 days prior to exercise. Participants completed an eccentric exercise procedure of the elbow flexors at 140% of 1-RM (6 sets x 10 repetitions). The time under tension (TUT) for each set of eccentric contractions was recorded manually from the investigators voice commands. Fasted blood samples for prostaglandin E2 (PGE2), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL1-ra), C-reactive protein and creatine kinase (CK) were assessed on days 1, 2 and 4. Fasted serum DHA was measured at baseline (day -28) and on day 1. Peak isometric strength of the elbow flexors, delayed-onset muscle soreness, and range of motion were measured on day 1 prior to exercise and days 2, 3, and 4 following exercise. Results: DHA significantly reduced natural log of CK (p<0.05) response over 4 d. Additionally, IL-6 area under the curve (AUC) was reduced for DHA compared to PL (3.6 ± 2.5 pg/mL vs. 5.3 ± 2.7 pg/mL) (p<0.05). TUT/set was higher in the DHA group compared to placebo (p<0.05). There were no other significant differences between treatments. Conclusion: DHA supplementation produced lower indicators of muscle damage (CK) and inflammation (IL-6 AUC). DHA supplementation resulted in greater TUT/set.<br>Master of Science
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Broch, i. Montané Montserrat. "Contribució de les citocines proinflamatòries, factor de necrosi tumoral alfa (tnea) i interleucina 6 (il-6), a la resistència a la insulina. Estudi serològic i genètic." Doctoral thesis, Universitat Rovira i Virgili, 2002. http://hdl.handle.net/10803/8748.
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La Diabetes mellitus tipo 2 (DM2) está causada principalmente por la disminución de la acción de la insulina (resistencia a la insulina) y por el deterioramiento de la función de las células beta. La DM2 y la obesidad se hallan íntimamente relacionadas. Así, el tejido adiposo es capaz de sintetizar y secretar diversas moléculas que se han visto implicadas en la modulación de la sensibilidad a la insulina (Si). Entre estas moléculas están las citocinas Factor de Necrosis Tumoral alfa (TNF) y la Interleucina 6 (IL-6).<br/>El TNF actúa mediante los receptores TNFR1 y TNFR2. La unión de la citocina a sus receptores forma las fracciones solubles de los receptores (sTNFR1 y sTNFR2)."In vivo", la inyección de esta citocina puede inhibir el transporte de glucosa al interior de la célula mediada por insulina. En animales obesos y/o diabéticos inducidos genéticamente existe una sobreexpresión de la citocina en el tejido adiposo y niveles circulantes de la proteína más elevados.<br/>En obesidad humana existe una sobrexpresión de TNF y de TNFR2 en tejido adiposo y niveles de las sTNFR2 circulantes aumentados. Estas sobreexpresiones se relacionan positivamente con el índice de masa corporal y los niveles de insulina, ambos marcadores de resistencia a la insulina.<br/>En cuanto a la IL-6, su infusión induce a hipertrigliceridemia "in vivo" y "in vitro". En humanos, la citocina se encuentra sobreexpresada en la obesidad y en la DM2, relacionándose con los marcadores clásicos de resistencia a la insulina. El alelo G del polimorfismo -174G>Cde la IL-6 se asocia a tasas de transcripción elevadas.<br/>Los trabajos que presentamos tienen como objetivo estudiar el sistema TNF y la IL-6 y su relación con la sensibilidad a la insulina.<br/>1. Plasma levels of the soluble fraction of tumor necrosis factor receptor 2<br/>and insulin resistance. Diabetes, 47:1757-62, 1998<br/>Los niveles de sTNFR2 son más elevados en población obesa (BMI >30 < 40 kg/m2) respecto de la delgada. Los niveles de sTNFR2 correlacionan positivamente con: BMI, masa muscular y glucosa basal, y negativamente con la sensibilidad a la insulina.<br/>2. Polymorphism of the tumor necrosis factor receptor 2 gene is associated with obesity, leptin levels, and insulin resistance in young subjects and diettreated type 2 diabetic patients. Diabetes Care, 23:831-837, 2000<br/>En una población con DM2 y una control analizamos la región 3'UTR del gen del TNFR2 y hallamos 4 variantes que identificamos por secuenciación. La variante A2 se asocia a niveles elevados de BMI y de leptina, sobre todo en la población joven (edad < a 54 años). En un subgrupo control se confirma que los portadores de A2 presentan una hipertrigliceridemia asociada a índices de sensibilidad a la insulina inferiores y una mayor razón cintura-cadera, ambas características típicas del síndrome metabólico.<br/>3. Interleukin-6 gene polymorphism and insulin sensitivity. Diabetes, 49:517-520, 2000<br/>Se analiza el polimorfismo -174G>C del gen de la IL-6 en población obesa (BMI<40 kg/m2). Los individuos portadores del alelo G, a pesar de ser comparables en edad, masa grasa y masa muscular, presentan niveles significativamente más elevados de hemoglobina glicosidada, insulina y glucosa, junto con una disminución de la sensibilidad la insulina.<br/>4. Interleukin-6 gene polymorphism and lipid abnormalities in healthy subjects. J Clin Endocrinol Metab 85:1334-1339, 2000<br/>La misma población que el estudio anterior se caracteriza deun perfil lipídico y se determinan los niveles de la IL-6. Los individuos portadores del alelo G presentan niveles más altos de triglicéridos y de ácidos grasos libres antes y después del test OGTT. Los niveles de IL-6 correlacionaron positivamente con estos parámetros lipídicos.<br/>Conclusiones:<br/>1- La determinación de los niveles de sTNFR2 podría presentarse como marcador de resistencia a la insulina<br/>2- La región 3'UTR del gen del TNFR2 podría ser marcador genético asociado al síndrome metabólico.<br/>3- El polimorfismo de restricción -174G>C del gen de la IL-6 podría participar en la predisposición genética del grado de resistencia a la insulina y de los niveles lipídicos.<br>Type 2 diabetes mellitus (DM2) was caused basically by the reduction of the insulin action (insulin resistance) and by the deterioration of the beta cells function. The DM2 and obesity are intimately related between them. In this way, the adipose tissue is able to synthesize and secrete various molecules that are related to the insulin sensitivity (Si) modulation such as Tumor Necrosis Factor-alfa (TNF) and interleukin-6 (IL-6).<br/>TNF- signals thorough at least two known cell-surface receptors: TNFR1 and TNFR2. The joining of the cytokine to their receptors derived to receptors soluble forms (sTNFR1 and sTNFR2). "In vivo" studies, cytokine supply could inhibit the insulin-stimulated glucose uptake. In genetic fat and /or diabetics animals there is an over-expression of this cytokine in fat tissue and in plasma.<br/>In obese patients, there is an over-expression of TNF and TNFR2 in fat tissue and of sTNFR2 in plasma. These over-expressions are related to the body mass index and insulin levels, both markers of insulin resistance.<br/>On the other hand, the IL-6 induces to hypertrygliceridemia "in vivo" and "in vitro".<br/>In humans, this cytokine is over-expressed in obese and DM2 patients and it is involved in the classical insulin resistance markers. G-allele of the -174G>C polymorphism has been found to be associated with elevated transcription rates.<br/>The goals of the presented studies are to analyse TNF system and IL-6 and their relation to insulin sensitivity.<br/>1. Plasma levels of the soluble fraction of tumor necrosis factor receptor 2 and insulin resistance. Diabetes, 47:1757-62, 1998<br/>Obese patients (BMI >30 < 40 kg/m2) showed increased plasma levels of sTNFR2 in comparison with lean. These levels are correlated positively with BMI, fat free mass and glucose levels; and related negatively with insulin sensitivity.<br/>2. Polymorphism of the tumor necrosis factor receptor 2 gene is associated with obesity, leptin levels, and insulin resistance in young subjects and diettreated type 2 diabetic patients. Diabetes Care, 23:831-837, 2000 3´ Untranslated region of the TNFR2 gene was analysed in DM2 and control populations. It was found four alleles identified by sequencing analysis. A2 allele exhibited significantly higher BMI and leptin levels in young population (younger than 54 years-old). In a subgroup of control subjects it was found that people with A2 allele showed several characteristics of the insulin resistance syndrome such as increased waist-to-hit ratio and hypertrygliceridemia in association with a lower insulin sensitivity index.<br/>3. Interleukin-6 gene polymorphism and insulin sensitivity. Diabetes, 49:517- 520, 2000<br/>It was analysed the -174G>C polymorphism IL-6 gene in obese patients (BMI<40 kg/m2). Subjects with G allele, despite the fact of being similar in age, fat mass and fat free mass in comparison with carrier of C allele, the first one showed significantly higher levels of blood HbA1c , insulin and glucose and lower Si <br/>4. Interleukin-6 gene polymorphism and lipid abnormalities in healthy subjects. J Clin Endocrinol Metab 85:1334-1339, 2000<br/>The same population than in the previous study was characterised through a lipidic profile and IL-6 levels were measured. Subjects carrying the G allele showed higher plasma levels of triglycerides and free fatty acids before and post OGTT test. Plasma IL-6 levels were significantly associated with these lipidic parameters.<br/>Conclusions<br/>1.- The measure of plasma sTNFR2 levels may be used as an insulin sensitivity marker<br/>2.- 3´untranslated region of TNFR2 gene may be used as a genetic marker associated with metabolic syndrome<br/>3.- -174G>C restriction polymorphism of IL-6 gene may be related with genetic predisposition to insulin sensitivity rate and to plasma lipids levels.
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Harré, Eva-Maria [Verfasser]. "Die Rolle von Interleukin-6 (IL-6) in der zentralnervös vermittelten Fieberentstehung der Ratte / Eva-Maria Harré." Wettenberg : VVB Laufersweiler, 2003. http://d-nb.info/968960545/34.
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Silva, Ítala Cristine. "Papel da interleucina 6 (IL-6) na resposta inflamatória neutrofílica durante a infecção por Leishmania infantum>." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17147/tde-06062017-170957/.
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As leishmanioses são um conjunto de doenças causadas pela infecção com protozoários do gênero Leishmania. No Brasil, o parasita L. infantum provoca a manifestação de uma doença sistêmica e crônica, conhecida como leishmaniose visceral (VL), que, quando não tratada, pode levar o indivíduo à óbito. A gravidade da leishmaniose visceral vem sendo associada ao aumento do nível sistêmico de IL- 6 em pacientes sintomáticos. Ainda não está claro como o aumento dessa citocina coordena a progressão da doença. Nós demonstramos durante a infecção por L. infantum experimental há produção dessa citocina nos órgãos alvos. Em decorrência dessa via, animais deficientes para IL-6 (IL-6-/-) são suscetíveis a infecção por apresentar maior número de parasitos nos órgãos alvo e por desenvolverem uma fraca resposta inflamatória em função da diminuição do infiltrado inflamatório. Como consequência, há o aumento de CXCL2 que medeia o recrutamento de neutrófilos no baço. Apesar de aumentada em animais IL-6-/- os neutrófilos apresentam um estado menos ativado. A produção dos principais mediadores de morte dos parasitos, como espécies reativas de oxigênio (ROS) e o óxido nítrico (NO), estão comprometidas e favorecem a disseminação do parasito em animais IL-6-/-. Por outro lado, a Il-6 não interfere na produção de citocinas pró-inflamatórias e na proliferação de linfócitos Th1, atuando somente em linfócitos Th17 no início da infecção, sugerindo que o controle da resposta inflamatória é dependente de mecanismos inatos. Em humanos, identificamos dois genes modulados pela via de sinalização da IL-6. Os genes Hsbp1 e AR estão up-regulados em pacientes com a doença ativa e são genes associados com a migração e a produção de neutrófilos na medula óssea, possivelmente envolvidos com a neutropenia em pacientes com LV. Juntos, os dados mostram que a via de sinalização da IL-6 tem papel importante na modulação da resposta imune de neutrófilos, e em promover proteção durante a LV.<br>Leishmaniasis is a group of diseases caused by infection with protozoa of the genus Leishmania. In Brazil, the parasite L. infantum causes the manifestation of a systemic and chronic disease, known as visceral leishmaniasis (VL), which, when left untreated, can lead to death. The severity of visceral leishmaniasis has been associated with an increase in the systemic level of IL-6 in symptomatic patients. It is not yet clear how the increase in this cytokine coordinates the progression of the disease. We demonstrated during the infection by experimental L. infantum there is production of this cytokine in the target organs. As a result of this pathway, IL-6 ( IL- 6-/-) deficient animals are susceptible to infection because they present a higher number of parasites in the target organs and they develop a poor inflammatory response due to the decrease of the inflammatory infiltrate. As a consequence, there is an increase in CXCL2 that mediates the recruitment of neutrophils in the spleen. Although increased in IL-6-/- animals the neutrophils have a less activated state. The production of the main mediators of parasite death, such as reactive oxygen species (ROS) and nitric oxide (NO), are compromised and favor the spread of the parasite in IL-6-/- animals. On the other hand, IL-6 does not interfere in the production of proInflammatory cytokines and Th1 lymphocyte proliferation, acting only on Th17 lymphocytes at the beginning of the infection, suggesting that the control of the inflammatory response is dependent on innate mechanisms. In humans, we identified two genes modulated by the IL-6 signaling pathway. The Hsbp1 and AR genes are up-regulated in patients with the active disease and are genes associated with the migration and production of neutrophils in the bone marrow, possibly involved with neutropenia in patients with VL. Together, the data show that the IL-6 signaling pathway plays an important role in modulating the neutrophil immune response, and in promoting protection during LV.
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Habowski, Scott. "Effects of the IL-6 Gene Polymorphism -174G/C on Interleukin-6 Production and Endurance Exercise Performance." Kent State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent1532023529854917.
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Hata, Hiroshi. "Distinct contribution of IL-6, TNF-α, IL-1, and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice". Kyoto University, 2005. http://hdl.handle.net/2433/145302.
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Holmes, Anna Greer, and not supplied. "Role of interleukin-6 in states of metabolic health and disease." RMIT University. Medical Sciences, 2006. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20070131.121620.
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Obesity and type 2 diabetes are the most prevalent metabolic diseases affecting over 50% of people in the western world. Although the pathogenesis of type 2 diabetes is not fully understood, growing evidence links this disease to a state of chronic inflammation, which occurs in metabolically active tissue such as the liver, adipose tissue and skeletal muscle and results in the secretion of inflammatory cytokines, of which interleukin-6 (IL-6) is one. It is generally accepted that elevations in the plasma and/or tissue of this family of cytokines have a negative effect on whole body glucose homeostasis. While there is compelling evidence for the negative effects of resistin and TNF-á on insulin sensitivity, the role of IL-6 in the etiology of insulin resistance is not fully understood. The notion of negative effects of IL-6 in metabolic processes is further confounded by the marked elevations of IL-6 which occur in conjunction with the beneficial activity of exercise. We firstly sought to examine the effect of the lipolytic hormone adrenaline on IL-6 expression and release in order to establish whether IL-6 acts independently of adrenaline in the regulation of fat metabolism. Reporting the absence of an effect of adrenaline on IL-6, we then investigated the role of IL-6 on metabolic processes in humans at rest and during exercise in circumstances where lipolysis was inhibited. Marked increases in IL-6 circulating protein and tissue gene expression were observed with exercise and further so with fatty acid suppression. In a mouse model of IL-6 depletion marked insulin sensitivity was observed, which was reversed with IL-6 treatment. In a mouse model with normal endogenous IL-6 levels IL-6 treatment also impaired glucose tolerance. Contrastingly, in a rat model both chronic and acute IL-6 treatment improved glucose tolerance In summary, studies from this thesis suggest that, rather than being causally related to insulin resistance, the cytokine IL-6 increases lipolysis, fat oxidation, and glucose metabolism in insulin sensitive tissues in humans. This does not appear to be the case in the mouse, where contrasting actions are observed, perhaps due to differences in the reliance of various parameters for metabolic processes between the species.
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Nguyen, Loan. "The role of interleukin-1 receptors in brain cell signalling." Thesis, University of Manchester, 2010. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-interleukin1-receptors-in-brain-cell-signalling(78c927ce-a654-4eac-b2d7-2ca4ca8c0fd4).html.
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IL-1α and IL-1β are two IL-1 agonists which signals at the same receptor complex composed of IL-1R1/IL-1RAcP. However, IL-1α and IL-1β exert differential actions. A recent CNS-specific IL-1 receptor accessory protein, called IL-1RAcPb, has been characterised but its actions are unknown. In T cell line, over expression of IL-1RAcPb negatively regulate IL-1 action (Smith et al, 2009), but over-expression of IL-1RAcPb in HEK cell line induces IL-1 signaling (Lu et al, 2008). The role of IL-1RAcPb has not been studied in primary cells. The aim of this project was to investigate the role of IL-1RAcPb in IL-1-induced actions in neurones and glia, and to determine IL-1α and IL-1β differential actions in these two cell types. The role of IL-1RAcPb in IL-1-induced protein expression and IL 1α and IL-1β differential effects were investigated by treating WT and IL 1RAcPb-/- neurones and glia with IL-1α or IL-1β in the presence or absence of IL-1RA for 24 h followed by assessment of IL-6 induction by ELISA. The mechanism of IL-1RAcPb actions were studied by examining the effects of IL-1α or IL-1β on p38, ERK1/2 and Src kinase activation in neurones and glia by Western blot analysis. SB203580 (p38 inhibitor), UO126 (ERK1/2 inhibitor), and PP2 (Src kinase inhibitor) were used to determine the contribution of p38, ERK1/2 and Src kinase activation to IL-1-induced IL-6 synthesis in neuronal cultures. In WT neurones, IL-1α and IL-1β were equipotent at inducing IL-6 synthesis and p38 activation, whilst both ligands failed to induce ERK1/2 or Src kinase activation. In IL-1RAcPb-/- neurones, IL-1α and IL-1β induced similar levels of IL-6, but IL-1β was more potent than IL-1α at inducing p38 activation. IL-1α-induced p38 activation was reduced in IL-1RAcPb-/- neurones compared to WT neurones. In contrast to WT neurones, ERK1/2 was activated in IL-1RAcPb-/- neurones in response to IL-1α, whilst Src kinase was not activated by IL-1α or IL 1β. IL-1-induced IL-6 synthesis was abolished by IL-1RA, SB203580, UO126 and PP2. Interestingly PP2, a specific Src kinase inhibitor also partially inhibited basal ERK1/2 activity. In WT glial cells, IL-1α was more potent than IL-1β at inducing IL-6 synthesis but both cytokines induced ERK1/2 activation with equal potency. In IL-1RAcPb-/- glia, IL-1α and IL-1β were equally potent at inducing IL-6 synthesis and ERK1/2 activation. However, IL-α-induced-IL-6 synthesis was reduced in IL 1RAcPb-/- glia compared to WT glia. In both WT and IL-1RAcPb-/- glia, IL-1α and IL-1β induced p38 activation but not Src kinase activation . In conclusion, this study showed that in neurones, IL-1RAcPb may contribute to IL-1α-induced p38 activation but negatively regulates IL-1-induced ERK1/2 activation, therefore IL-1RAcPb may have specific effects on different signalling pathways. The effect of IL-1RAcPb could also be cell specific, as IL 1RAcPb contributed to IL-1α-induced p38 signalling in neurones but IL-6 production in glia. The role of IL-1RAcPb remains largely unknown and more investigations are required to elucidate its role in IL-1 signalling in the brain.
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Gagnon, Julien. "Les effets synergiques des cytokines pro-inflammatoires et des cytokines impliquées dans l’homéostasie sur les réponses des lymphocytes T CD8 aux antigènes." Thèse, Université de Sherbrooke, 2016. http://hdl.handle.net/11143/8777.
Full textAbstract:
Résumé : L’IL-7 et l’IL-15 sont des cytokines impliquées dans l’homéostasie des lymphocytes T CD8 naïfs et mémoires respectivement. Lors d’une réponse immunitaire, certaines cytokines pro-inflammatoires, comme l’IL-6 et l’IL-21, sont produites par les cellules du système immunitaire inné. Nous avons observé que certaines cytokines de ces deux groupes (homéostasie et pro-inflammatoires), peuvent avoir un effet synergique sur la fonction des lymphocytes T CD8. Spécifiquement, l’incubation des lymphocytes T CD8 naïfs avec l’IL-6 ou l’IL-21, en présence d’IL-7 ou d’IL-15 cause une forte prolifération qui est indépendante de l’antigène. De plus, la combinaison d’IL-15 avec l’IL-6 ou l’IL-21 entraîne une prolifération préférentielle des lymphocytes T mémoires, tandis que la combinaison avec l’IL-7 entraîne une prolifération des lymphocytes T naïfs. La stimulation des lymphocytes T CD8 avec l’IL-6 ou l’IL-21, en présence d’IL-7 ou d’IL-15, entraîne une augmentation de la phosphorylation en tyrosine de STAT5 ainsi qu’une augmentation de liaison à l’ADN. Nous avons étudié l’effet d’une pré-stimulation des cellules T CD8 naïves par les cytokines synergiques sur leur réponse subséquente à un antigène. Nous avons observé qu’une pré-stimulation avec l’IL-6 ou l’IL-21, en présence d’IL-7 ou d’IL-15, même pour une courte durée de 24 heures, augmente leur sensibilité aux antigènes, entraînant une robuste prolifération et une forte augmentation de cytotoxité spécifique à l’antigène gp33. Nous avons observé que les cytokines pro-inflammatoires en combinaison avec l’IL-7 induisent une augmentation accrue de la prolifération chez les lymphocytes T CD8 exprimant un TCR transgénique de forte affinité (P14), ainsi que les cellules exprimant un TCR de faible affinité (H-Y). De plus, la combinaison synergique de cytokines entraîne une forte expression du récepteur de l’IL-2R[gamma] (CD132), ainsi qu’une augmentation de la production d’IL-2 après stimulation antigénique. Une forte augmentation de l’expression de CD8 et de CD45, ainsi qu’une diminution drastique de l’expression de CD5 peut expliquer l’augmentation de l’avidité fonctionnelle du TCR suite à une stimulation avec les combinaisons de cytokines synergiques. La stimulation des lymphocytes T CD8 avec les combinaisons de cytokines, induit une augmentation de la phosphorylation de LAT ainsi qu‘AKT. Cependant, la stimulation subséquente du CD3 n’entraîne pas d’augmentation de la phosphorylation de LAT ainsi qu’AKT chez les lymphocytes T CD8 pré-stimulés avec les combinaisons de cytokines. Nous avons aussi observé que les lymphocytes T CD8 stimulés avec les combinaisons de cytokines augmentent l’expression de CD62L, ce qui peut favoriser leur migration vers les ganglions lymphatiques. En conclusion, la production de cytokines pro-inflammatoires (IL-6, IL-15, IL-21) par les cellules du système immunitaire inné lors d’une infection ou d’une inflammation, ainsi que la présence constitutive d’IL-7, peuvent stimuler la prolifération et l’activation des lymphocytes T CD8 de façon non spécifique à l’antigène. Cette stimulation entraîne une augmentation de l’avidité fonctionnelle de leur TCR causant ainsi une forte prolifération ainsi que l’acquisition de fonctions effectrices spécifiques. Cette liaison entre le système immunitaire inné et adaptatif, médiée par les cytokines pro-inflammatoires et les cytokines homéostatiques joue un rôle très important dans l’élimination des pathogènes ainsi que dans le développement de maladies auto-immunitaires.<br>Abstract : Homeostasis of naive and memory CD8[superscript +] T lymphocytes is dependent on two cytokines IL-7 and IL-15, respectively. During an immune response to an infection, cells of the innate immune system produce several pro-inflammatory cytokines. We have observed that these two groups of cytokines, namely proinflammatory and homeostatic, can have a synergistic effect on CD8 T lymphocytes. Specifically, incubation of naive CD8 T cells with IL-6 or IL-21 in the presence of IL-7 or IL-15 induced strong proliferation in an antigen independent manner. While the combination of IL-6 or IL-21 with IL-15 induced strong proliferation of memory CD8 T cells, naïve CD8 T cells responded better to the combination with IL-7. These stimulatory cytokine combinations elicited strong STAT5 phosphorylation and it’s binding to DNA in CD8 T cells. We investigated the effect of priming CD8 T cells with the synergistic combination of IL-6 or IL-21 and IL-7 on their subsequent response to antigen. We observed that cytokine priming for only 24 hours enhanced their sensitivity to antigen, resulting in strong proliferation, effectors functions and cytotoxicity. These effects were observed with CD8 T cells expressing transgenic TCR with strong (P14) or weak (H-Y) affinity towards cognate peptide antigens. Priming CD8 T cells with the synergistic combination of cytokines increased the expression of IL-2 receptor gamma (CD132) and augmented the production of IL-2 when stimulated with antigen. These cells also expressed elevated levels of CD8 and CD45, as well as down modulate CD5, and these events may underlie the increased TCR avidity. Stimulation of CD8 T cells with the synergistic combination of cytokines induced phosphorylation of LAT and AKT. However, subsequent TCR stimulation did not further increase these phosphorylation events. We have observed that C D8 T cells primed with the synergistic combinations of cytokines up regulated CD62L, which could promote their migration through lymph nodes. In conclusion, inflammatory cytokines such as (IL-6, IL-15, IL-21) secreted by cells of the innate immune system during an infection or non-infectious inflammation, and basal levels of the homeostatic cytokine IL-7 can act in synergy with inflammatory cytokines to activate CD8 T lymphocytes in an antigen independent manner. This stimulation also results in an increase in the functional avidity of their TCR, as indicated by strong antigen responsiveness with increased proliferation and display of effectors functions. This connection between the innate and adaptive system mediated by inflammatory cytokines may play an important role in pathogen clearance and possibly in the development of autoimmune diseases.