Dissertations / Theses on the topic 'Leukotrienes'

Cysteinyl leukotriene receptor 2, a G-protein coupled receptor known to be expressed and functional on human platelets. However, it seems that upon ligand activation the cysteinyl leukotriene receptor 2 activates a variety of signaling pathways in multiple cell types among different species. Previously, a former laboratory member Vrinda Kulkarni found cysteinyl leukotriene receptor 2 to be expressed on the surface of adult zebrafish thrombocytes. In this work I studied the characteristics of aggregation in adult zebrafish thrombocytes with the knockdown of cysteinyl leukotriene receptor 2. I used a newly developed knockdown method to study the function of cysteinyl leukotriene receptor 2. Knockdown of the cysteinyl leukotriene was confirmed using RT-PCR results showed p=.001, reduced sell surface level of expression of the cysteinyl leukotriene receptor 2 results showed that p=.002. I found that the knockdown of cysteinyl leukotriene receptor 2 results in prothrombotic thrombocytes by using flow cytometry p=.0001.

La déstabilisation de la plaque d’athérosclérose reste de nos jours un problème majeur, malgré les progrès récents dans sa compréhension. Les neutrophiles sont des acteurs puissants de l’immunité innée capables d’altérer les plaques. Un chimio-attractant majeur des neutrophiles, le leucotriène B4, pourrait être un des contributeurs potentiels de la déstabilisation des plaques en particulier dans l’endotoxémie, elle-même associée aux accidents cardiovasculaires. L’objectif de ce travail a été de définir le rôle du leucotriène B4 dans l’attraction des neutrophiles dans la plaque au cours de l’endotoxémie et de déterminer si les neutrophiles peuvent basculer l’équilibre qui maintient les plaques stables. Nous avons montré que le recrutement des neutrophiles médié par le leucotriène B4 a un impact délétère sur la stabilité des plaques au cours de l’endotoxémie en favorisant l’apoptose et la dégradation de fibres matricielles. En conclusion, cette étude ouvre la voie vers de nouvelles approches thérapeutiques visant à cibler l’axe leucotriène-neutrophiles dans la maladie athérosclérotique
Atherosclerotic plaque destabilisation remains an important issue, in spite of the recent advances in its comprehension. Neutrophils are powerful innate immune actors capable of altering plaques. In this context, the leukotriene B4, one of the main chemoattractants of neutrophils, has been proposed as a potential contributor to plaque destabilisation. A particular context in which these two actors are closely linked is endotoxemia, itself associated with plaque destabilisation This work was aimed at determining whether leukotriene B4 plays a role in the chemoattraction of neutrophils in plaques during endotoxemia and at assessing whether neutrophils can tip the balance which maintains plaques stable. We have herein evidenced that the recruitment of neutrophils mediated by leukotriene B4 has a deleterious impact upon plaque stability during endotoxemia by promoting apoptosis and degrading matrix fibres. In conclusion, this study paves the way to novel therapeutic approaches aimed at targeting the axis leukotriene-neutrophil in atherosclerotic disease

Membrane proteins are involved in a number of disease pathologies and thus comprise a large number of drug targets. Determination of the high-resolution three-dimensional structure is essential for rational drug design, but several hurdles need to be overcome, primarily the over-expression and purification of said membrane proteins. Human leukotriene C4 synthase (hLTC4S), an 18 kDa integral membrane protein localized in the outer nuclear membrane of eosinophils and basophils, catalyzes the conjugation of LTA4 and reduced glutathione to produce LTC4. LTC4 and its metabolites LTD4 and LTE4 are the cysteinyl leukotrienes implicated in bronchoconstriction and inflammation pathways. The focus of my project involves optimizing the over-expression and purification of hLTC4S, which was heterologously expressed in Schizosaccharomyces pombe, purified by immobilized affinity chromatography, and finally "polished" with a buffer exchange step to remove excess co-purified lipids. The optimized protocol yielded ~1 mg of ~90% homogenous, pure protein per liter of cell culture. The finalized purified protein can then be used for further investigation of two-dimensional crystals by electron crystallography with the overall goal of structure determination.

Antigen-specific Th2 cells are central to the pathogenesis of asthma and other allergic diseases. Th2 cells secrete the cytokines IL-4, IL-5 and IL-13, responsible for many of the features of allergic inflammation such as eosinophilia, IgE production and mucus hypersecretion. Cysteinyl leukotrienes (CysLTs) are known potent lipid mediators involved in mucus production, bronchoconstriction and leukocyte migration, and act via the receptors CysLTiR and CysLT2R. Recently, CysLTs have been implicated in Th2 responses in mouse models, although the exact mechanisms are unclear. Preliminary microarray studies on polarised human Thl and Th2 cells suggested a highly selective expression of CYSLTR1 by human Th2 cells. Subsequent RT-PCR analysis confirmed that Th2 cells selectively express CYSLTR1 mRNA at high levels. Calcium signalling experiments revealed that Th2 cells respond selectively to leukotrienes compared to Thl cells, with a rank order of potency similar to that reported for CysL R (LTD4>LTC4>LTE4). This profile of leukotrienes responsiveness was blocked using the known selective CysLTiR antagonists MK571, Montelukast and Zafirlukast. Additionally, the LTD4-induced signalling in Th2 cells is mediated via CysLTiR coupled to Gaq and Gaj proteins, which are blocked when using selective CysLTiR antagonists. Finally, LTD4 is a potent chemoattractant for Th2 cells, which migrate to LTD4 at low nanomolar concentrations in a dose-dependent manner. Migration of human Th2 cells towards LTD4 was inhibited by selective CysLTiR antagonist MK571. Interestingly, LTD4 had no significant effect on the proliferation or differentiation of Th2 cells, or on the expression of Th2-specific cytokines. Microarray studies on LTD4-treated Th2 cells identified key immediate early genes that were upregulated after 30 minutes of treatment, and that were differentially expressed compared to untreated cells. This is the first report that human T cell subsets express functional CysLTiR and important implications for our understanding of the anti-inflammatory effect mechanism of CysLTiR antagonists.

No presente trabalho verificamos o papel dos Leucotrienos na modulação da resposta imune durante a fase aguda da infecção experimental pelo Trypanosoma cruzi, usando como modelo camundongos deficientes da enzima 5-lipoxigenase (5-LOko). Os nossos dados demonstram que camundongos infectados pelo T. cruzi produzem metabólitos do ácido aracdônico como PGE2, LTB4 e LTC4. Comparados aos animais controles, os animais 5-LOko apresenta parasitemia mais tardia e menor, tem menor parasitismo tissular, menor infiltrado de células inflamatórias no coração e musculatura esquelética e apresenta menor taxa de mortalidade durante a fase aguda, indicando que animais deficientes de leucotrienos são mais resistentes a infecção pelo parasito. Animais 5-LOko está relacionado com a manutenção de números elevados de células F4/80+ e redução de células CD11b+ durante a infecção e menor número de células T ativadas expressando os marcadores CD4+CD69+, CD4+CD25+, CD4+CD44+ e CD8+CD69+, números inalterados de células T regulatórias CD4+CD25+GITR+ e menor produção de anticorpos parasito-específicos do isotipo IgG2a. O controle eficiente de parasitas por animais 5-LOko está associado ao aumento de células Gr-1+ e CD11c+GR-1+, produção aumentada IL-12, IFN-g, e produzirem menos PGE2, IL-10, ao contrario, animais controles, incapazes de controlar parasitas circulantes, produzem mais PGE2 e IL-10 e menos IL-12 e IFN-g. A baixa mortalidade de animais 5-LOko correlaciona com a produção de PGE2 e IL-10, produzir muita IL-12 e menos IFN-g e NO e baixíssima parasitemia. A mortalidade maior de animais controles envolve a produção IFN-g e altos níveis de LTB4, LTC4, NO e ausência de IL-10, IL-1b, PGE2 e números elevados de parasitas circulantes. Ainda macrófagos de animais 5-LOko apresentam maior capacidade de adesão/internalização de tripomastigotas e alta atividade tripanocida por mecanismo independente da geração de NO. Estes dados em conjunto demonstram que mediadores lipídicos produzidos pela enzima 5-lipoxigenase como LTB4 e LTC4 modulam negativamente a capacidade dos camundongos para geração de uma resposta imune capaz de controlar os parasitos durante a fase aguda da infecção pelo T. cruzi.
Accumulating studies have indicated that 5-lipoxigenase (5-LO) converted lipid mediators as leukotrienes acts modulating the host immune response against infectious diseases. The precise role of leukotrienes during the protozoan infection is unknown. In this work we evaluate the role of leukotrienes during the acute phase of Trypanosoma cruzi infection using as model the 5-lypoxigenase deficient mice (5-LOko). Our results show that PGE2, LTB4 and LTC4 are produced during the Trypanosoma cruzi infection. 5-LOko infected mice are more resistant than control mice as judge by the lower parasitemia, decreased number of parasite nest and inflammatory cells in the heart and skeletal muscle and low rate of mortality. The resistance of 5-LOko mice is associated with the increased capacity of spleen cells to produce cytokines as IL-12 and IFN-g; sustained capacity to produce detectable levels of IL-10 and PGEe and low NO serum levels than control mice. In contrast, the wild type mice are extremely susceptible and are unable to control parasites efficiently. The susceptibility is associated with increased levels of IL-10 and PGE2 and low IL-12 and IFN-g production. The high mortality rate in wild type mice is related with high LTB4, LTC4 and NO levels and bias to produce only type 1 cytokines. Also we shown that resistant 5-LOko mice present increased number of spleen cells expressing GR-1+, GR-1+CD11c+, F4/80+ and lower numbers o spleen cells expressing CD4+CD69+, CD4+CD25+, CD4+CD44+, CD8+CD69+ and CD11b+ and low serum levels of parasite-specific IgG2a than wild type mice and do not present alteration in TREG expressing CD4+CD25+GITR+. Importantly, IFN-g and- LPS activated macrophage from 5-LOko mice but not from wild type mice, present high capacity to recognize typomastigotes, internalize them and strong capacity to kill intracellular parasite as NO independent pathway. The results implicate that high levels leukotrienes, NO and pure type 1 cytokines production is associated to susceptibility to parasite. In contrast, leukotrienes deficiency led to an balanced immune response with relative high levels of type 1 cytokines and relative low levels of NO, type 2 cytokines and PGE2 that efficiently control the parasites. Also indicate that 5-lipoxigenase converted lipid mediators contribute negatively to generation of an effective immune response during the acute phase of T. cruzi infection.

Increased bulk of smooth muscle mass around the airways is a typical feature of asthma. Several mediators act in concert or antagonistically to regulate airway smooth muscle (ASM) cell proliferation. This thesis focuses on fibroblast growth factor (FGF)2 and transforming growth factor (TGF)[béta]1 which are known to be sequentially upregulated in the lung following allergic challenge and have recently been shown to synergize together in ASM cell proliferation. Emphasis is put toward the conflicting studies documenting the mitogenic effect of TGF[béta]1 in vitro and to its seemingly potent effect in vivo. Thereafter, different asthma mediators, such as IL-4 and IL-13, are introduced and how their mitogenic potential toward ASM cells could be altered by FGF2 is presented. Finally, how the controversial issue between in vitro and in vivo data regarding the mitogenic effect of leukotrienes could be reconciliated and how it could be related to FGF2 and TGF[béta]1 proliferative synergism is discussed.

Kyoto University (京都大学)
0048
新制・課程博士
博士(人間・環境学)
甲第12400号
人博第318号
新制||人||79(附属図書館)
17||D||177(吉田南総合図書館)
24236
UT51-2006-J392
京都大学大学院人間・環境学研究科相関環境学専攻
(主査)教授 五十棲 泰人, 助教授 倉橋 和義, 教授 津田 謹輔
学位規則第4条第1項該当

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Universidade Estadual Paulista (UNESP)
Leucotrienos são mediadores clássicos da resposta inflamatória, descritos como agentes quimiotáticos e reguladores da atividade microbicida de células do sistema imune inato, tendo papel protetor contra diferentes agentes infecciosos. Neste estudo, nós investigamos o envolvimento de leucotrienos no curso da paracoccidioidomicose murina a partir dos seguintes parâmetros imunológicos: influxo celular, atividade da mieloperoxidase, produção de NO, produção de citocinas e recuperação fúngica em pulmões de camundongos selecionados de acordo com a intensidade da sua resposta inflamatória aguda máxima (AIRmax) e mínima (AIRmin). Observamos que a infecção por P. brasiliensis induz considerável produção de citocinas IL-6, IL-10, IFN- e TNF-, promove o recrutamento celular e produção de NO nos pulmões em diferentes períodos de estudo. Nos animais tratados com um inibidor as síntese de leucotrienos (MK886) observamos uma menor produção das citocinas IFN-, IL-6 e TNF- concomitante com a queda do influxo de neutrófilos, e também diminuição na produção de NO, esses resultados podem explicar uma maior carga fungica nos pulmões de animais que tiveram a síntese de leucotrienos inibida, sugerindo aos leucotrienos um possível papel protetor na paracoccidioidomicose experimental. Animais da linhagem AIRmax apresentaram menor carga fungica quando comparado com animais AIRmin, este resultado pode ser relacionado ao fenótipo da AIR quanto à migração de neutrófilos, além de uma menor produção de NO e citocinas pró-inflamatórias, conferindo aos camundongos com background AIRmax maior resistência a infecção por P.brasiliensis.
Leukotrienes are classic inflammatory response mediators considered chemotactic agents and microbicide activity regulators in cells of the innate immune system, playing a protective role against different infectious agents. In this study, we investigated the involvement of leukotrienes in the course of murine paracoccidioidomycosis based on the following immunologic parameters: cell influx, mieloperoxydase activity, NO production, cytokine production, and fungal recovery in lungs of mice selected according to the intensity of their low (AIRmin) and high (AIRmax) acute inflammatory response. Infection by P. brasiliensis induced considerable production of the cytokines IL-6, IL-10, IFN-, and TNF-, and led to cell recruitment, as well as NO production, in lungs at different study periods. In animals treated with MK886, a leukotriene biosynthesis inhibitor, IFN-, IL-6 and TNF- production was lower, while neutrophil influx and NO production decreased. These results may explain the higher fungal load in lungs of animals in which leukotriene synthesis was inhibited, suggesting that leukotrienes have a possible protective role in experimental paracoccidioidomycosis. AIRmax animals had lower fungal load relative to AIRmin ones, which can be related to the AIR phenotype regarding neutrophil migration, besides lower production of NO and pro-inflammatory cytokines; thus, mice presenting AIRmax background are more resistant to infection by P.brasiliensis.

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The knowledge about immunology of Leishmania (Viannia) braziliensis-murine infection is poorly known, especially concerning innate immune response and the involvement of leukotrienes in the resistance mechanisms. Leukotrienes are lipid mediators of inflammation that activate microbicidal mechanisms in leukocytes. The present study aimed to evaluate the BALB/c and C57Bl/6 murine infection with two L. (V.) braziliensis isolates obtained from cutaneous leishmaniasis patients and the involvement of leukotrienes in the resistance of infection. Thus, IMG3 and RPL5 isolates were identified as L. (V.) braziliensis by using molecular techniques and the in vitro growth of parasites in Grace´s medium (26°C) was evaluated. The time course of lesion after footpad infection was followed in BALB/c and C57Bl/6 mice. C57Bl/6 mice genetically deficient in interferon gamma (IFNγ) were infected to evaluate the relevance of this cytokine in resistance. The parasite burden in draining lymph nodes and spleens was detected by limiting dilution assay. BALB/c- and C57Bl/6-infected footpads were processed after 12 weeks of infection and those from IFNγ-defecient mice after 4 weeks for histopathological analyses. Tissue sections were stained by hematoxylin-eosin. Parasite capacity to induce nitric oxide (NO) was analyzed in RAW 264.7 cell cultures treated or not with IFNγ and lipopolysaccharide (LPS). Nitrites were detected by using Griess reaction. The NO modulation by endogenous leukotrienes was evaluated through treatment of the cultures with a 5-lipoxygenase (5-LO) inhibitor and a leukotriene B4 (LTB4) antagonist. Macrophage leishmanicidal activity against IMG3 isolate was evaluated in thioglycolateelicited peritoneal macrophages of C57Bl/6 mice. In these cultures, NO was inhibited by aminoguanidine. In vivo leukotriene inhibition was achieved by using a 5-LO inhibitor. In vitro-parasite growth profiles were similar and parasites at the 5th day of culture were used to infection. The lesion course was also similar between isolates in both two mouse stains used, but C57Bl/6 mice presented healing after 12 weeks of infection whereas in BALB/c mice the lesion was persistent. In IFNγ-deficient mice there progressive lesions and visceralization in IMG3- as well as in RPL5-infected mice. Corroborating these data, the parasite burden in draining lymph nodes of BALB/c mice was higher than in C57Bl/6 mice after 12 weeks of infection with IMG3, and parasites (IMG3 and RPL5) were identified in about 50% of the IFNγ-deficient mouse spleens. The histopathological analyses showed an intense dermal infiltrate with vacuolated macrophages heavily parasitized in BALB/c mice (12 weeks) an in IFNγ-deficient mice (4 weeks), but not in C57Bl/6 mice (12 weeks), similarly for IMG3 and RPL5. Both isolates IMG3 an RPL5 induced NO production in RAW 264.7 celll cultures presenting synergism with IFNγ. Endogenous leukotrienes did not affect NO production in these cultures. C57Bl/6 peritoneal macrophages activated with IFNγ/LPS killed IMG3 parasites depending on NO release. In vivo inhibition of leukotriene synthesis did not change the course of infection in C57Bl/6 mice infected with IMG3 isolate. The relevant findings are: BALB/c mouse is susceptible to infection with IMG3 an RPL5 isolates whereas C57Bl/6 is resistant; IFNγ is crucial to the control of the infection; the isolates induce NO and this molecule contributes to macrophage leishmanicidal activity; and also the data suggest that endogenous leukotrienes are not involved in the control of L. (V.) braziliensis in C576Bl/6 mouse.
A imunologia da infecção murina por Leishmaia (Viannia) braziliensis é pouco conhecida, especialmente considerando a imunidade inata e a participação dos leucotrienos nos mecanismos de resistência à infecção. Os leucotrienos são mediadores lipídicos da inflamação que ativam mecanismos microbicidas dos leucócitos. O presente trabalho teve como objetivo avaliar o perfil da infecção de camundongos BALB/c e C57Bl/6 por dois isolados de L. (V.) braziliensis obtidos de pacientes com leishmaniose cutânea e o envolvimento dos leucotrienos endógenos na resistência à infecção. Para isto, os isolados denominados IMG3 e RPL5 foram identificados como L. (V.) braziliensis por meio de técnicas moleculares e foram avaliados quanto ao crescimento in vitro em meio Grace (26°C), e quanto ao curso da evolução da lesão, em camundongos BALB/c e em C57Bl/6. Camundongos C57Bl/6 geneticamente deficientes em interferon gama (IFNγ) foram infectados para avaliar a importância desta citocina no controle da infecção. A carga parasitária foi obtida pelo ensaio da diluição limitante em linfonodos drenantes da lesão e nos baços. As patas dos camundongos BALB/c e C57Bl/6 foram colhidas após 12 semanas de infecção, e dos camundongos deficientes em IFNγ, na 4ª semana, e foram processadas para análises hitopatológicas. A capacidade de indução de óxido nítrico (NO) pelos isolados foi avaliada em culturas de células RAW 264.7 tratadas ou não com IFNγ e lipopolissacarídeo (LPS), sendo os nitritos detectados por reação de Griess. A regulação da produção de NO pelos leucotrienos endógenos foi avaliada por tratamento das culturas de macrófagos com um inibidor de 5-lipoxigenase (5-LO) e um antagonista de receptor de leucotrieno B4 (LTB4). A atividade microbicida dos macrófagos foi avaliada em macrófagos peritoneais (C57Bl/6) infectados com o isolado IMG3, sendo o NO inibido por aminoguanidina. O efeito da inibição de leucotrienos, in vivo, foi avaliado em camundongos C57Bl/6 infectados com o isolado IMG3 e tratados com um inibidor de 5- LO. As curvas de crescimento in vitro foram similares para os dois isolados e os parasitos no 5° dia de cultivo foram usados nos experimentos de infecção. O curso da lesão foi similar entre os dois isolados nos camundongos BALB/c e C57Bl/6, porém enquanto a lesão regrediu nos C57Bl/6, nos camundongos BALB/c, a lesão foi persistente até a 12ª semana de infecção. Em camundongos deficientes em IFNγ houve crescimento progressivo das lesões e visceralização, tanto com o isolado IMG3 quanto com o RPL5. Confirmando estes dados, a carga parasitária nos linfonodos drenantes da lesão nos camundongos BALB/c foi maior do que a encontrada nos C57Bl/6 após 12 semanas de infecção com IMG3 e os parasitos (IMG3 e RPL5) foram encontrados em cerca de 50% dos baços dos camundongos deficientes em IFNγ. As análises histopatológicas mostraram um acentuado infiltrado inflamatório na derme, com macrófagos vacuolizados repletos de parasitos nos camundongos BALB/c (12 semanas), e nos deficientes de IFNγ (4 semanas), mas não nos camundongos C57Bl/6 (12 semanas), similarmente para IMG3 e RPL5. Os isolados IMG3 e RPL5 induziram NO em células RAW 264.7 em sinergismo com IFNγ e os leucotrienos endógenos não alteraram a produção de NO destas células. Macrófagos peritoneais murinos mostraram atividade microbicida de maneira dependente de NO. A inibição in vivo da síntese de leucotrienos não alterou o curso da infecção pelo isolado IMG3 em camundongos C57Bl/6. Coletivamente, os dados mostram que o camundongo BALB/c é suscetível à infecção pelos dois isolados, enquanto o C57Bl/6 é resistente; o IFNγ é essencial para o controle da infecção; os isolados induzem a produção de NO, o qual contribui para a eliminação dos parasitos; e os dados sugerem que os leucotrienos endógenos não estão envolvidos nos mecanismos de resistência dos camundongos C57Bl/6 a L. (V.) braziliensis.

Leucotrienos (LTs) são mediadores lipídicos derivados do ácido araquidônico. Existem evidências que receptores da imunidade inata interagem com receptores para LTs amplificando funções efetoras de macrófagos. Investigamos se LTs modulam a fagocitose e a atividade microbicida via receptores Manose, Dectina -1 e PTX3 em macrófagos alveolares (AMs) e os mecanismos moleculares envolvidos. Nossos resultados mostram que: 1) AMs sintetizam LTs quando fagocitam C. albicans, Zy e Zy-PTX3; 2) LTs potencializam a fagocitose de C. albicans e Zy, mas não de Zy-PTX3. Este efeito dos LTs depende: do reconhecimento via receptor manose (LTB4) e Dectina-1 (LTD4); da integridade de lipid rafts; da ação em mecanismos de polimerização de actina; do aumento dos níveis de F-actina por inativação da Cofilina-1; da ativação das LIMKs, que regulam Cofilina-1; da ativação de PKCd e PI3K3) LTs aumentam a capacidade de AMs em matar C. albicans por ativação de NADPH oxidase. Em conjunto, mostramos que LTs potencializam programas de sinalização específicos para determinados PRRs.
Leukotrienes (LTs) are lipid mediators derived from arachidonic acid. There is evidence that innate immunity receptors and leukotrienes receptors interact and amplify macrophage effector functions. We investigated if LTs receptors modulate phagocytosis and microbicidal activity mediated by Mannose receptor, Dectin-1 and PTX3 in alveolar macrophages (AMs) and the molecular mechanisms involved. Our results showed that: 1) AMs produce LTs when stimulated with C.albicans, Zy, Zy-PTX3; 2) LTs enhance phagocytosis of C.albicans and Zymosan, but not Zy-PTX3. This is dependent on: recognition via mannose receptor (LTB4) and Dectin-1 (LTD4); integrity of lipid rafts; its action on actin polimerization mechanisms; enhancement of F-actin levels by induction of Cofilin-1 inactivation; activation of LIMKs that regulate Cofilin-1; activation of PKCd and PI3K3) LTs enhance killing of C.albicans by activation of NADPH oxidase. Taken together, our results showed that LTs specifically influence signaling programs of keys PRRs.