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1
Chung, Soo-Hyun, Xiao-Qi Ye, and Yoichiro Iwakura. "Interleukin-17 family members in health and disease." International Immunology 33, no. 12 (October 6, 2021): 723–29. http://dx.doi.org/10.1093/intimm/dxab075.
Повний текст джерелаАнотація:
Abstract The interleukin-17 (IL-17) family consists of six family members (IL-17A–IL-17F) and all the corresponding receptors have been identified recently. This family is mainly involved in the host defense mechanisms against bacteria, fungi and helminth infection by inducing cytokines and chemokines, recruiting neutrophils, inducing anti-microbial proteins and modifying T-helper cell differentiation. IL-17A and some other family cytokines are also involved in the development of psoriasis, psoriatic arthritis and ankylosing spondylitis by inducing inflammatory cytokines and chemokines, and antibodies against IL-17A as well as the receptor IL-17RA are being successfully used for the treatment of these diseases. Involvement in the development of inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and tumors has also been suggested in animal disease models. In this review, we will briefly review the mechanisms by which IL-17 cytokines are involved in the development of these diseases and discuss possible treatment of inflammatory diseases by targeting IL-17 family members.
2
Kleinschek, Melanie A., Alexander M. Owyang, Barbara Joyce-Shaikh, Claire L. Langrish, Yi Chen, Daniel M. Gorman, Wendy M. Blumenschein, et al. "IL-25 regulates Th17 function in autoimmune inflammation." Journal of Experimental Medicine 204, no. 1 (January 2, 2007): 161–70. http://dx.doi.org/10.1084/jem.20061738.
Повний текст джерелаАнотація:
Interleukin (IL)-25 is a member of the IL-17 family of cytokines. However, unlike the other members of this family, IL-25 promotes T helper (Th) 2 responses. We now show that IL-25 also regulates the development of autoimmune inflammation mediated by IL-17–producing T cells. We have generated IL-25–deficient (il25−/−) mice and found that they are highly susceptible to experimental autoimmune encephalomyelitis (EAE). The accelerated disease in the il25−/− mice is associated with an increase of IL-23 in the periphery and a subsequent increase in the number of inflammatory IL-17–, IFNγ-, and TNF-producing T cells that invade the central nervous system. Neutralization of IL-17 but not IFNγ in il25−/− mice prevented EAE, suggesting that IL-17 is a major disease-promoting factor. IL-25 treatment at several time points during a relapse-remitting model or chronic model of EAE completely suppressed disease. IL-25 treatment induced elevated production of IL-13, which is required for suppression of Th17 responses by direct inhibition of IL-23, IL-1β, and IL-6 expression in activated dendritic cells. Thus, IL-25 and IL-17, being members of the same cytokine family, play opposing roles in the pathogenesis of organ-specific autoimmunity.
3
Han, Q., S. Das, M. Hirano, S. J. Holland, N. McCurley, P. Guo, C. S. Rosenberg, T. Boehm, and M. D. Cooper. "Characterization of Lamprey IL-17 Family Members and Their Receptors." Journal of Immunology 195, no. 11 (October 21, 2015): 5440–51. http://dx.doi.org/10.4049/jimmunol.1500892.
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4
Towne, Jennifer E., Yu Zhang, Lori A. Siegel, Antony Symons, and Alison L. Budelsky. "PS2-045. Role of IL-17 family members in psoriasis." Cytokine 56, no. 1 (October 2011): 75. http://dx.doi.org/10.1016/j.cyto.2011.07.205.
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5
Majumder, Saikat, and Mandy J. McGeachy. "IL-17 in the Pathogenesis of Disease: Good Intentions Gone Awry." Annual Review of Immunology 39, no. 1 (April 26, 2021): 537–56. http://dx.doi.org/10.1146/annurev-immunol-101819-092536.
Повний текст джерелаАнотація:
The IL-17 family is an evolutionarily old cytokine family consisting of six members (IL-17A through IL-17F). IL-17 family cytokines signal through heterodimeric receptors that include the shared IL-17RA subunit, which is widely expressed throughout the body on both hematopoietic and nonhematopoietic cells. The founding family member, IL-17A, is usually referred to as IL-17 and has received the most attention for proinflammatory roles in autoimmune diseases like psoriasis. However, IL-17 is associated with a wide array of diseases with perhaps surprisingly variable pathologies. This review focuses on recent advances in the roles of IL-17 during health and in disease pathogenesis. To decipher the functions of IL-17 in diverse disease processes it is useful to first consider the physiological functions that IL-17 contributes to health. We then discuss how these beneficial functions can be diverted toward pathogenic amplification of deleterious pathways driving chronic disease.
6
Li, H., J. Chen, A. Huang, J. Stinson, S. Heldens, J. Foster, P. Dowd, A. L. Gurney, and W. I. Wood. "Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family." Proceedings of the National Academy of Sciences 97, no. 2 (January 18, 2000): 773–78. http://dx.doi.org/10.1073/pnas.97.2.773.
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7
Paroli, Marino, Luca Spadea, Rosalba Caccavale, Leopoldo Spadea, Maria Pia Paroli, and Nicola Nante. "The Role of Interleukin-17 in Juvenile Idiopathic Arthritis: From Pathogenesis to Treatment." Medicina 58, no. 11 (October 28, 2022): 1552. http://dx.doi.org/10.3390/medicina58111552.
Повний текст джерелаАнотація:
Background and Objectives: Interleukin-17 (IL-17) is a cytokine family consisting of six members and five specific receptors. IL-17A was the first member to be identified in 1993. Since then, several studies have elucidated that IL-17 has predominantly pro-inflammatory activity and that its production is involved in both the defense against pathogens and the genesis of autoimmune processes. Materials and Methods: In this review, we provide an overview of the role of interleukin-17 in the pathogenesis of juvenile idiopathic arthritis (JIA) and its relationship with IL-23, the so-called IL-23–IL-17 axis, by reporting updated findings from the scientific literature. Results: Strong evidence supports the role of interleukin-17A in the pathogenesis of JIA after the deregulated production of this interleukin by both T helper 17 (Th17) cells and cells of innate immunity. The blocking of IL-17A was found to improve the course of JIA, leading to the approval of the use of the human anti-IL17A monoclonal antibody secukinumab in the treatment of the JIA subtypes juvenile psoriatic arthritis (JPsA) and enthesitis-related arthritis (ERA). Conclusions: IL-17A plays a central role in the pathogenesis of JIA. Blocking its production with specific biologic drugs enables the effective treatment of this disabling childhood rheumatic disease.
8
Cho, Mila, Seon-Yeong Lee, Jin-Sil Park, Hye-Joa Oh, Hye-Jin Son, Jun-Geol Ryu, and Ho-Youn Kim. "Up-Regulation of Stromal Cell-Derived Factor by IL-17 and IL-18 via Phosphatidylinositol 3-Kinase Dependent Pathway (171.8)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 171.8. http://dx.doi.org/10.4049/jimmunol.188.supp.171.8.
Повний текст джерелаАнотація:
Abstract IL-17 producing Th17 has a key role in the pathogenesis of autoimmune inflammation. Among various cytokines which are interwoven with the IL-17 pathway, members of IL-1beta family including IL-18 have recently gained significance. In the present study, we stimulated synovial fibroblasts with the combination of IL-17 and IL-18, and quantified the cellular production of stromal cell-derived factor-1 (SDF-1) with ELISA and its mRNA with RT-PCR. Both IL-17 and IL-18 significantly increased the level of SDF-1, not only individually but also synergistically (p<0.05). The synergism was effectively suppressed by anti-IL-17, anti-IL-18 antibodies and PI3K inhibitor. In conclusion, PI3K-dependent synergism between IL-18 and IL-17 is first observed in this study, and adds a novel perspective for the role of IL-18 in immune regulation. The two cytokines’ individual effects, mutual interaction and synergism draw a crisscrossing map between IL-1 family and IL-17.
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Guo, Yifei, Wei Cao, and Ying Zhu. "Immunoregulatory Functions of the IL-12 Family of Cytokines in Antiviral Systems." Viruses 11, no. 9 (August 22, 2019): 772. http://dx.doi.org/10.3390/v11090772.
Повний текст джерелаАнотація:
Members of the interleukin 12 (IL-12) family have been known to be inflammatory factors since their discovery. The IL-12 family consists of IL-12, IL-23, IL-27, IL-35, and a new member, IL-39, which has recently been identified and has not yet been studied extensively. Current literature has described the mechanisms of immunity of these cytokines and potential uses for therapy and medical cures. IL-12 was found first and is effective in combatting a wide range of naturally occurring viral infections through the upregulation of various cytokines to clear the infected cells. IL-23 has an essential function in immune networks, can induce IL-17 production, and can antagonize inhibition from IL-12 in the presence of T helper (Th) 17 cells, resulting in type II IFN (IFN-γ) regulation. IL-27 has a competitive relationship to IL-35 because they both include the same subunit, the Epstein–Barr virus-induced gene3 (EBi3). This review provides a simple introduction to the IL-12 family and focuses on their functions relevant to their actions to counteract viral infections.
10
Broxmeyer, Hal E., Trevor Starnes, Heather Ramsey, Scott Cooper, Richard Dahl, Elizabeth Williamson, and Robert Hromas. "The IL-17 cytokine family members are inhibitors of human hematopoietic progenitor proliferation." Blood 108, no. 2 (July 15, 2006): 770. http://dx.doi.org/10.1182/blood-2006-01-0292.
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11
Krohn, Sonja, Jasper F. Nies, Sonja Kapffer, Tilman Schmidt, Jan-Hendrik Riedel, Anna Kaffke, Anett Peters, et al. "IL-17C/IL-17 Receptor E Signaling in CD4+ T Cells Promotes TH17 Cell-Driven Glomerular Inflammation." Journal of the American Society of Nephrology 29, no. 4 (February 26, 2018): 1210–22. http://dx.doi.org/10.1681/asn.2017090949.
Повний текст джерелаАнотація:
The IL-17 cytokine family and the cognate receptors thereof have a unique role in organ-specific autoimmunity. Most studies have focused on the founding member of the IL-17 family, IL-17A, as the central mediator of diseases. Indeed, although pathogenic functions have been ascribed to IL-17A and IL-17F in the context of immune-mediated glomerular diseases, the specific functions of the other IL-17 family members in immunity and inflammatory kidney diseases is largely unknown. Here, we report that compared with healthy controls, patients with acute Anti-neutrophil cytoplasmatic antibody (ANCA)-associated crescentic glomerulonephritis (GN) had significantly elevated serum levels of IL-17C (but not IL-17A, F, or E). In mouse models of crescentic GN (nephrotoxic nephritis) and pristane-induced lupus nephritis, deficiency in IL-17C significantly ameliorated the course of GN in terms of renal tissue injury and kidney function. Deficiency of the unique IL-17C receptor IL-17 receptor E (IL-17RE) provided similar protection against crescentic GN. These protective effects associated with a reduced TH17 response. Bone marrow transplantation experiments revealed that IL-17C is produced by tissue-resident cells, but not by lymphocytes. Finally, IL-17RE was highly expressed by CD4+ TH17 cells, and loss of this expression prevented the TH17 responses and subsequent tissue injury in crescentic GN. Our findings indicate that IL-17C promotes TH17 cell responses and immune-mediated kidney disease via IL-17RE expressed on CD4+ TH17 cells. Targeting the IL-17C/IL-17RE pathway may present an intriguing therapeutic strategy for TH17-induced autoimmune disorders.
12
Jackson, Shawn, Ada Undieh, Harold Steiner, Zuly Parra, Robert Miller, Yuko Ohta та Martin Flajnik. "Ontogenic analysis of Xenopus γδ T cells: expressed T cell receptor (TCR) γ and δ chains and IL-17 family members (160.8)". Journal of Immunology 188, № 1_Supplement (1 травня 2012): 160.8. http://dx.doi.org/10.4049/jimmunol.188.supp.160.8.
Повний текст джерелаАнотація:
Abstract γδ TCR that have structural differences from conventional γδ TCR in mammals have been observed in non-eutherian vertebrates. Three different types of Vδ regions are present in Xenopus tropicalis, similar to Vδ, Vα, and VHδ (derived from the V regions of Ig H chains). Semi-quantitative PCR analyses in adult and larval Xenopus laevis show that expression levels of TCRδC and TCRγC, as well as of TCRδV and TCRγV repertoires, vary between tissues. Comparative analyses of adult and larval CDR3 sequences suggest ontogenic-, tissue- and perhaps V family-specific expression. We have detected changes at the VDJ junctions including N-nucleotide addition, nucleotide trimming, and homologous recombination events. γδ T cell populations in mammals differentially express either IL-17 or IFNγ. In mammals, six IL-17 forms have been described (A-E), the least well characterized of which is IL-17D. Most non-mammalian IL-17 homologs, including those in chicken, fish, lamprey, nematode, oyster, sea urchin, and tunicate, and especially, Xenopus, are the IL-17D form. We have cloned two types of IL-17A/F, IL-17B, and IL-17D from X. laevis. Semi-quantitative PCR analyses in adult and larval Xenopus show that the expression of these IL-17 family members vary during ontogeny and between tissues. Study of γδ TCR and IL-17 family expression in Xenopus will illuminate evolutionary and developmental changes in γδ T cell antigen recognition and effector strategies.
13
Pires, Bruno R. B., Renata Binato, Gerson M. Ferreira, Stephany Corrêa, Bárbara Du Rocher, Daniel Bulzico, Susanne Crocamo, Everton Cruz dos Santos, Luize G. Lima, and Eliana Abdelhay. "Twist1 Influences the Expression of Leading Members of the IL-17 Signaling Pathway in HER2-Positive Breast Cancer Cells." International Journal of Molecular Sciences 22, no. 22 (November 10, 2021): 12144. http://dx.doi.org/10.3390/ijms222212144.
Повний текст джерелаАнотація:
Breast cancer (BC) is a heterogeneous disease composed of multiple subtypes with different molecular characteristics and clinical outcomes. The metastatic process in BC depends on the transcription factors (TFs) related to epithelial-mesenchymal transition (EMT), including the master regulator Twist1. However, its role beyond EMT in BC subtypes remains unclear. Our study aimed to investigate the role of Twist1, beyond EMT, in the molecular subtypes of BC. In patients, we observed the overexpression of TWIST1 in the HER2+ group. The silencing of TWIST1 in HER2+ BC cells resulted in the upregulation of 138 genes and the downregulation of 174 genes compared to control cells in a microarray assay. In silico analysis revealed correlations between Twist1 and important biological processes such as the Th17-mediated immune response, suggesting that Twist1 could be relevant for IL-17 signaling in HER2+ BC. IL-17 signaling was then examined, and it was shown that TWIST1 knockdown caused the downregulation of leading members of IL-17 signaling pathway. Taken together, our findings suggest that Twist1 plays a role on IL-17 signaling in HER2+ BC.
14
Bosmann, Markus, Fabien Meta, Robert Ruemmler, Mikel D. Haggadone, J. Vidya Sarma, Firas S. Zetoune, and Peter A. Ward. "Regulation of IL-17 Family Members by Adrenal Hormones During Experimental Sepsis in Mice." American Journal of Pathology 182, no. 4 (April 2013): 1124–30. http://dx.doi.org/10.1016/j.ajpath.2013.01.005.
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15
González-Fernández, Carmen, Elena Chaves-Pozo, and Alberto Cuesta. "Identification and Regulation of Interleukin-17 (IL-17) Family Ligands in the Teleost Fish European Sea Bass." International Journal of Molecular Sciences 21, no. 7 (March 31, 2020): 2439. http://dx.doi.org/10.3390/ijms21072439.
Повний текст джерелаАнотація:
Interleukin-17 (IL-17) cytokine comprises a family of six ligands in mammals with proinflammatory functions, having an important role in autoimmune disorders and against bacterial, viral, and fungal pathogens. While IL-17A and IL-17F ligands are mainly produced by Th cells (Th17 cells), the rest of the ligands are expressed by other immune and non-immune cells and have different functions. The identification of IL-17 ligands in fish has revealed the presence of six members, counterparts to mammalian ones, and a teleost-specific form, the fish IL-17N. However, tissue distribution, the regulation of gene expression, and scarce bioactivity assays point to similar functions compared to mammalian ones, though this yet to be investigated and confirmed. Thus, we have identified seven IL-17 ligands in the teleost European sea bass (Dicentrarchus labrax), for the first time, corresponding to IL-17A/F1, IL-17A/F2, IL-17A/F3, IL-17C1, IL-17C2, IL-17D, and IL-17N, according to the predicted protein sequences and phylogenetic analysis. They are constitutively and widely transcribed in sea bass tissues, with some of them being mainly expressed in the thymus, brain or intestine. Upon in vitro stimulation of head-kidney leucocytes, the mRNA levels of all sea bass IL-17 ligands were up-regulated by phytohemagglutinin treatment, a well-known T cell mitogen, suggesting a major expression in T lymphocytes. By contrast, the infection of sea bass juveniles with nodavirus (NNV), a very pathogenic virus for this fish species, resulted in the up-regulation of the transcription of IL-17C1 in the head-kidney and of IL-17C1 and IL-17D in the brain, the target tissue for NNV replication. By contrast, NNV infection led to a down-regulated transcription of IL-17A/F1, IL-17A/F2, IL-17C1, IL-17C2, and IL-17D in the head-kidney and of IL-17A/F1 and IL-17A/F3 in the brain. The data are discussed accordingly with the IL-17 ligand expression and the immune response under the different situations tested.
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Yu, Jeffrey J., Matthew J. Ruddy, Grace C. Wong, Cornelia Sfintescu, Pamela J. Baker, Jeffrey B. Smith, Richard T. Evans, and Sarah L. Gaffen. "An essential role for IL-17 in preventing pathogen-initiated bone destruction: recruitment of neutrophils to inflamed bone requires IL-17 receptor–dependent signals." Blood 109, no. 9 (January 3, 2007): 3794–802. http://dx.doi.org/10.1182/blood-2005-09-010116.
Повний текст джерелаАнотація:
AbstractIL-17 and its receptor are founding members of a novel family of inflammatory cytokines. IL-17 plays a pathogenic role in rheumatoid arthritis (RA)–associated bone destruction. However, IL-17 is also an important regulator of host defense through granulopoiesis and neutrophil trafficking. Therefore, the role of IL-17 in pathogen-initiated bone loss was not obvious. The most common form of infection-induced bone destruction occurs in periodontal disease (PD). In addition to causing significant morbidity, PD is a risk factor for atherosclerotic heart disease and chronic obstructive pulmonary disease (COPD). Similar to RA, bone destruction in PD is caused by the immune response. However, neutrophils provide critical antimicrobial defense against periodontal organisms. Since IL-17 is bone destructive in RA but a key regulator of neutrophils, we examined its role in inflammatory bone loss induced by the oral pathogen Porphyromonas gingivalis in IL-17RA–deficient mice. These mice showed enhanced periodontal bone destruction, suggesting a bone-protective role for IL-17, reminiscent of a neutrophil deficiency. Although IL-17RA–deficient neutrophils functioned normally ex vivo, IL-17RA knock-out (IL-17RAKO) mice exhibited reduced serum chemokine levels and concomitantly reduced neutrophil migration to bone. Consistently, CXCR2KO mice were highly susceptible to alveolar bone loss; interestingly, these mice also suggested a role for chemokines in maintaining normal bone homeostasis. These results indicate a nonredundant role for IL-17 in mediating host defense via neutrophil mobilization.
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O'Sullivan, Timothy, Robert Saddawi-Konefka, and Jack Bui. "IL-17D mediated cancer rejection (162.26)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 162.26. http://dx.doi.org/10.4049/jimmunol.188.supp.162.26.
Повний текст джерелаАнотація:
Abstract Immune system interaction with cancers can either enhance or prevent tumor formation. Cytokine secretion by immune infiltrates and tumor cells are important in regulating this process. IL-17A, a pro-inflammatory member of the IL-17 family, has been shown to have conflicting results in regards to cancer progression or regression. Other members of the IL-17 family, such as IL-17D, have no known roles in immune responses to cancer, or endogenous function. Our lab possesses matched methylcholanthrene (MCA)-induced tumor cell lines that will continuously grow (Progressors) or reject (Regressors) after transplantation into syngeneic WT mice. The regresssor cell lines can grow in immune-deficient RAG2-/- mice, indicating that their rejection in WT mice requires an intact immune system. Our lab has used these cell lines to identify differential cytokine expression profiles from microarray analysis. We have obtained data that shows IL-17D transcript and protein are significantly overexpressed in regressor cell lines when compared to progressor cell lines. Overexpression of IL-7D in progressor tumor cell lines leads to their rejection in WT mice in a NK cell dependent manner. We hypothesize that IL-17D expression in regressor cell lines leads to immune-mediated tumor rejection by recruiting NK cells that polarize M1 macrophages in the tumor microenvironment.
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Singh, Sujay, Hyun-Ku Lee, Gita Singh, Yi Feng Luo, Sriram Chitta та Jonathan Rosenberg. "Development of IL-17A promoter-based reporter cell line and activation of the cell line by exogenous expression of RORγ and RORγt. (59.12)". Journal of Immunology 188, № 1_Supplement (1 травня 2012): 59.12. http://dx.doi.org/10.4049/jimmunol.188.supp.59.12.
Повний текст джерелаАнотація:
Abstract As one of the six known IL-17 family members, IL-17A is a proinflammatory cytokine secreted by innate and adaptive immune cells. Especially IL-17A has been characterized as a key cytokine produced in a new CD4+ T helper subset, Th17 cells, which play an important role in host defense against specific pathogens. Effect of IL-17A is also implicated with pathogenic role of Th17 cells in autoimmunity and the chronic activation of IL-17-producing T helper cells can lead to autoimmune diseases. Indeed, increased levels of IL-17 have been observed in patients with autoimmune diseases including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and psoriasis as shown by researchers. Hence development of a targeted therapeutic means or molecule that can effectively control IL-17 induction is crucial to prevent the initiation of IL-17-producing cell-mediated autoimmune diseases. In response to this, we have developed the IL-17A Prom/LUCPorter™ HEK 293 cell line, in which Renilla luciferase reporter gene is under control of the inducible IL-17A promoter. This cell line has been validated by exogenous expression of RORγ or RORγt construct, which can induce the IL-17A promoter activity leading to expression of luciferase reporter protein. This cell line is suitable for screening of antagonists for IL-17A induction which can be utilized as the therapeutic target molecules to control IL-17-producing cells.
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Malhotra, Nidhi, Kavitha Narayan, Katelyn Sylvia, Heather Melichar та Joonsoo Kang. "WNT signaling programs the development of IL-17 producing γδ T cells and Innate Lymphoid Cells (115.17)". Journal of Immunology 188, № 1_Supplement (1 травня 2012): 115.17. http://dx.doi.org/10.4049/jimmunol.188.supp.115.17.
Повний текст джерелаАнотація:
Abstract IL-17/IL-22 producing γδ T cells and other innate lymphoid cell (ILC) subsets safeguards the mucosal epithelia of oral, reproductive, respiratory and intestinal tracts against infection and damages. γδ T cell subsets originate in the thymus and are exported as pre-made effectors, while the other ILC effector subsets differentiate in the gut associated lymphoid tissues. Whether a common gene network program distinct from that operating in adaptive T cells controls IL-17/IL-22 production in all innate lymphoid effectors is unknown. We demonstrate that sry high mobility group (HMG) box transcription factors (TFs), SOX13 and other family members, function in a positive loop to control the intrathymic differentiation of IL-17 producing γδ T cells. In contrast, another HMG TF TCF1, the nuclear effector of canonical WNT signaling, is the primary negative regulator of the network. Furthermore, we show that TCF1 is also required for the functional differentiation of ILCs. Together, the results suggest the existence of a TF network that controls all innate IL-17 producing effectors, independent of tissue origin and T cell antigen receptor expression, distinct from that involved in generating IL-17 producing adaptive T cells.
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Umemura, Masayuki, Masayuki Fukui, Chiho Fukui, Susumu Nakae, Yoichiro Iwakura, and Goro Matsuzaki. "Role of IL-17 in chronic pulmonary mycobacterial infection. (MPF1P.775)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 66.14. http://dx.doi.org/10.4049/jimmunol.192.supp.66.14.
Повний текст джерелаАнотація:
Abstract IL-17 family cytokine is comprised of six members, IL-17A to IL-17F. Recent studies using cytokine- and receptor-deficient mice showed that IL-17A and IL-17F were required for responses to extracellular bacterium K. pneumonia in the lungs and C. rodentium in the colon, respectively. However, the involvement of IL-17A and IL-17F in protective immunity was well not clearly demonstrated in mycobacterial infected lung. In this study, we analyzed role of IL-17A and IL-17F in host defense against chronically infected M. tuberculosis. using IL-17A- and IL-17F-KO mice. The IL-17A-KO mice showed significantly decreased survival rates compared with the wild-type (WT) mice during 250-day observation period. In contrast, survival rate of the IL-17F-KO mice were similar to that of the WT mice. Bacterial burdens of various organs of the IL-17F-KO mice on the day 250 were nearly the same as that in the WT mice. In the infected lungs, the IL-17A-KO mice produced less IFN-γ, TNF and IL-6 in comparison to those from the WT mice, while cytokine production of the IL-17F-KO mice were similar to that of the WT mice. This result indicated that the generation of Th1 cells was impaired in the IL-17A-KO mice but not in the IL-17F-KO mice infected with M. tuberculosis. These data strongly support the notion that the lack of IL-17F neither suppress nor enhances protective immunity in the lung after mycobacterial infection.
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Fabre, Joseph, Jérôme Giustiniani, Stéphanie Servagi-Vernat, Christian Garbar, Yacine Merrouche, Frank Antonicelli, and Armand Bensussan. "Interleukin 17 in the tumor microenvironment: A potent target for anticancer immunotherapy?" Journal of Clinical Oncology 35, no. 7_suppl (March 1, 2017): 115. http://dx.doi.org/10.1200/jco.2017.35.7_suppl.115.
Повний текст джерелаАнотація:
115 Background: Inflammation has been known to play a critical role in cancer for decades. Tumors build up on the “inflammatory soup” in the surrounding microenvironment to progress, grow, metastasize and evade immune response. Since its discovery in the nineties, interleukin-17 (IL-17A), a proinflammatory cytokine mainly secreted by T helper 17 cells, has been extensively studied in chronic inflammatory diseases like psoriasis or rheumatoid arthritis. In solid malignancies, there is growing evidence that IL-17 enhances cancer cells’ capacity of division, invasion and chemotherapy resistance. Methods: Based on our team's experience and publications, we systematically reviewed the existing literature about the role of IL-17 in cancers, in aim to discuss if developing IL-17 pathway-targeting strategies could be effective. Results: Data from several preclinical studies indicated tumor-promoting effects of IL-17 on diverse cancer models, cellular or murine. In clinical studies, detection of high levels of IL-17 in patients’ blood or tumors was correlated to bad prognosis. Concordantly, we reported recently in triple negative breast cancer cell lines that IL-17A and IL-17E promoted resistance to Docetaxel and failed to induce apoptosis as previously observed for IL-17E by other authors. Interestingly, we also revealed that both cytokines induced the generation of tumorigenic low molecular weight forms of cyclin E (LMW-E), which high levels correlated strongly with a poor survival in breast cancer patients. Lastly, we reported a crosstalk between IL-17E and epidermal growth factor signaling, which confers in vitro resistance to EGFR-targeted therapies. In opposition, a few studies observed that IL-17 inhibited tumor grafts development and metastasis in rodent possibly through the expression of other proinflammatory mediators such as IL-1β, TNFα, IL-6 or GM-CSF and the recruitment of neutrophils to the tumor site. Conclusions: Most of the literature supports a critical role of IL-17 in cancer promotion and development. These results encourage us to present the IL-17 family members and their receptors as potent targets for anticancer biotherapy.
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Kato, Atsushi, Regina T. Chustz, and Robert P. Schleimer. "Regulation and function of newly-recognized IL-1 family cytokines in human bronchial epithelial cells (98.18)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 98.18. http://dx.doi.org/10.4049/jimmunol.182.supp.98.18.
Повний текст джерелаАнотація:
Abstract The IL-1 family of cytokines, which now includes 11 members, is well known to participate in inflammation. Although the latest IL-1 family cytokines (IL1F5-11) have been shown to be expressed in airway epithelial cells, the regulation of their expression has not been studied. We investigated the regulation of IL1F5-11 in normal human bronchial epithelial cells. Messenger RNAs for IL1F6 and IL1F9, but not IL1F5 or IL1F10, were significantly up-regulated by TNF, IL-1b, IL-17 and TLR3 ligand dsRNA. Messenger RNAs for IL1F7, IL1F8 and IL1F11 (IL-33) were weakly up-regulated by some of the cytokines tested. Notably, mRNAs for IL1F6 and IL1F9 were synergistically enhanced by the combination of TNF/IL-17 or dsRNA/IL-17. IL1F9 protein was detected in the supernatant following stimulation with dsRNA (1.6 ng/ml) or a combination of dsRNA and IL-17 (2.5 ng/ml). IL1F6 protein was detected by western blot. We screened the receptors for IL1F6 and IL1F9 and found that fibroblasts expressed these receptors. We found that IL1F9 activated the MAPKs and the transcription factors including NFkB in primary normal human lung fibroblasts. IL1F9 also stimulated the induction of CXCL8 and CCL20. These results suggest that epithelial activation by respiratory viral infection and exposure to cytokines from Th17 cells (IL-17) may amplify neutrophilic inflammation in the airway via induction of IL1F6 and IL1F9.
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Paroli, Marino, Rosalba Caccavale, Maria Teresa Fiorillo, Luca Spadea, Stefano Gumina, Vittorio Candela, and Maria Pia Paroli. "The Double Game Played by Th17 Cells in Infection: Host Defense and Immunopathology." Pathogens 11, no. 12 (December 15, 2022): 1547. http://dx.doi.org/10.3390/pathogens11121547.
Повний текст джерелаАнотація:
T-helper 17 (Th17) cells represent a subpopulation of CD4+ T lymphocytes that play an essential role in defense against pathogens. Th17 cells are distinguished from Th1 and Th2 cells by their ability to produce members of the interleukin-17 (IL-17) family, namely IL-17A and IL-17F. IL-17 in turn induces several target cells to synthesize and release cytokines, chemokines, and metalloproteinases, thereby amplifying the inflammatory cascade. Th17 cells reside predominantly in the lamina propria of the mucosa. Their main physiological function is to maintain the integrity of the mucosal barrier against the aggression of infectious agents. However, in an appropriate inflammatory microenvironment, Th17 cells can transform into immunopathogenic cells, giving rise to inflammatory and autoimmune diseases. This review aims to analyze the complex mechanisms through which the interaction between Th17 and pathogens can be on the one hand favorable to the host by protecting it from infectious agents, and on the other hand harmful, potentially generating autoimmune reactions and tissue damage.
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Fu, Yongyao, and Mark H. Kaplan. "Defining the mechanism of BATF specificity in Th cell lineages." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 171.8. http://dx.doi.org/10.4049/jimmunol.200.supp.171.8.
Повний текст джерелаАнотація:
Abstract IL-9 is a pleiotropic cytokine produced by Th9 cells and inappropriate expression is associated with immune disorders. The basic leucine zipper transcription factor (BATF) is expressed in multiple Th subsets and cooperates with other factors to regulate gene transcription. BATF-deficiency results in diminished IL-9 in Th9 cells and decreased IL-17 in Th17 cells. However, ectopic expression of BATF activates only the lineage-specific cytokine; IL-9 in Th9 cells and IL-17 in Th17 cells. The mechanism for this restricted activity is unclear. In this study, we demonstrate a lineage specific mechanism of how BATF activates Il9 in Th9 and Th17 cells. Using ChIP and chromatin accessibility assays we found that BATF binds to the Il9 gene locus at a greater level in Th9 cells compared to Th17 cells. This observation may be because the DNA in Th17 cells is in a heterochromatic state. Increasing the chromatin accessibility of Il9 gene locus in Th17 cells followed by BATF overexpression leads to increased IL-9 production. BATF forms a heterodimer with Jun family members to induce gene expression. The expression level of c-Jun and JunB in Th17 cells is lower compared to Th9 cells. In testing the role of these factors, we observed that the loss of c-Jun or JunB impairs IL-9 production in Th9 cells, indicating that Jun family members promote IL-9 production. Ectopic expression of BATF with either c-Jun or JunB significantly increases IL-9 production in Th17 cells, suggesting the low expression of Jun family members limits the ability of BATF to induce IL-9 in Th17 cells. Taken together, our results reveal a mechanism for how BATF achieves specificity of cytokine induction in Th subsets.
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Díez-Ricote, Laura, Paloma Ruiz-Valderrey, Víctor Micó, Ruth Blanco, Joao Tomé-Carneiro, Alberto Dávalos, José M. Ordovás, and Lidia Daimiel. "TMAO Upregulates Members of the miR-17/92 Cluster and Impacts Targets Associated with Atherosclerosis." International Journal of Molecular Sciences 23, no. 20 (October 11, 2022): 12107. http://dx.doi.org/10.3390/ijms232012107.
Повний текст джерелаАнотація:
Atherosclerosis is a hallmark of cardiovascular disease, and lifestyle strongly impacts its onset and progression. Nutrients have been shown to regulate the miR-17/92 cluster, with a role in endothelial function and atherosclerosis. Choline, betaine, and L-carnitine, found in animal foods, are metabolized into trimethylamine (TMA) by the gut microbiota. TMA is then oxidized to TMAO, which has been associated with atherosclerosis. Our aim was to investigate whether TMAO modulates the expression of the miR-17/92 cluster, along with the impact of this modulation on the expression of target genes related to atherosclerosis and inflammation. We treated HepG-2 cells, THP-1 cells, murine liver organoids, and human peripheral mononuclear cells with 6 µM of TMAO at different timepoints. TMAO increased the expression of all analyzed members of the cluster, except for miR-20a-5p in murine liver organoids and primary human macrophages. Genes and protein levels of SERPINE1 and IL-12A increased. Both have been associated with atherosclerosis and cardiovascular disease (CDVD) and are indirectly modulated by the miR-17-92 cluster. We concluded that TMAO modulates the expression of the miR-17/92 cluster and that such modulation could promote inflammation through IL-12A and blood clotting through SERPINE1 expression, which could ultimately promote atherosclerosis and CVD.
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Ahn, Inhye, and Ji Hyeon Ju. "Up-regulation of stromal cell-derived factor by il-17 and il-18 via PI3K dependent pathway." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 3046. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3046.
Повний текст джерелаАнотація:
3046 Background: Stromal cell-derived factor-1 (SDF-1) is a versatile chemotactic cytokine and a sole ligand of CXCR4. SDF-1-CXCR4 axis is the most commonly expressed pathway in cancer cells, and is also responsible for metastasis, homing of stem cell, HIV infection, and autoimmune diseases. Interleukin (IL)-17 plays a key role in the pathogenesis of inflammation by inducing SDF-1 to propagate inflammation and vascular endothelial growth factor to provoke angiogenesis. Recent studies revealed that IL-17 pathway is interwoven with multiple cytokines and downstream pathways. Members of the IL-1β family, including IL-18, have recently gained attention. By measuring SDF-1 production regulated by individual and simultaneous cytokine stimulations, two cytokines were explored to define their effects, their downstream signal transduction pathways, and the impact of their antibodies. Methods: Synovial tissue was obtained from patients with rheumatoid arthritis and their age- and sex-matched controls with osteoarthritis. Fibroblast-like synoviocytes (FLS) were isolated and stimulated with a combination of IL-17 and IL-18 and quantified SDF-1 production with ELISA and their transcripts with RT-PCR. Another subset of FLS were preconditioned with PI3K inhibitor, 100 nM wortmannin, and stimulated with either 5 ng/mL of IL-17, 10 ng/mL of IL-18, or combination of both cytokines. Mann-Whitney test was adopted for statistical analysis. Results: Both IL-17 and IL-18 increased SDF-1 level and its mRNA transcript, not only individually but also synergistically (p <0.05). In the group where PI3K inihibitor was applied, the individual and synergistic promotion of SDF-1 production by IL-17 and IL-18 were inhibited (p<0.05). Concomitant application of anti-IL-17 and anti-IL-18 led to further decline of SDF-1 production (p<0.01). Conclusions: This is the first report of PI3K-dependent synergism between IL-18 and IL-17, and adds a novel perspective of the role of IL-18 in immune regulation. The individual effects of these two cytokines, and their interaction through PI3K, suggest an interrelationship between the IL-1 family and IL-17.
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Schifano, Matthew, Soha Araji, Shourong Li, Natalie Ruiz, Nicolas Schrantz, Qiulong Huang, and Peggy Just. "A novel monoclonal antibody against the human IL-17AF heterodimer for flow cytometry (59.11)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 59.11. http://dx.doi.org/10.4049/jimmunol.188.supp.59.11.
Повний текст джерелаАнотація:
Abstract The IL-17 family members, IL-17A and IL-17F, are signature Th17 cytokines. Although they were both originally found to be produced as disulfide-linked homodimers, recent studies have confirmed the production of IL-17AF heterodimers in in vitro-differentiated and polarized Th17 cells. While ELISA-based assays have become available for the study of these heterodimers, flow antibodies have been generated only to the monomeric subunits, making discrimination between the homo- and heterodimer complexes difficult. Here, for the first time, we use a novel monoclonal antibody to identify producers of the IL-17AF heterodimer by flow cytometry. Under our polarization conditions, the majority of human lymphocytes that stain for both IL-17A and IL-17F also stain for the IL-17AF heterodimer. These results suggest that this population produces mostly IL-17AF heterodimers and not the IL-17A and IL-17F homodimers alone. This novel reagent will help expand our knowledge of the IL-17/Th17 axis and contribute to the elucidation of its role in the immune response.
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Prabhala, Rao H., Mariateresa Fulcinitti, Dheeraj Pelluru, Harsha K. Prabhala, Naim Rashid, Adam Sperling, Puru Nanjappa, et al. "Multiple Myeloma Cells Express IL-17A Creating An Autocrine Loop: An Attractive Therapeutic Target." Blood 122, no. 21 (November 15, 2013): 3113. http://dx.doi.org/10.1182/blood.v122.21.3113.3113.
Повний текст джерелаАнотація:
Abstract We have previously demonstrated that Th17 cells, which produce IL-17A, are significantly elevated in peripheral blood and bone marrow (BM) of patients with Multiple Myeloma (MM) and IL-17A promotes MM cell growth and survival, both in vitro and in vivo via IL-17A receptor. We have recently evaluated and observed that anti-IL-17A monoclonal antibody (mAb) significantly inhibited MM cell growth in vitro, while IL-17A induced proliferation of MM cells compared to control. We have also observed significant down-regulation of IL-6 production by anti-IL-17A mAb in MM-BMSC co-culture. Importantly, the administration of anti-IL-17A mAb weekly for 4 weeks in the SCIDhu model of human myeloma, where MM cells grow within the human microenvironment in mice led to a significant inhibition of tumor growth compared to the control mice. This remarkable activity of anti-IL17 mAb raised the question of whether the myeloma cells themselves are a possible source of IL-17. In this study, we used transcriptome sequencing (RNA-Seq) data to evaluate the expression of IL-17A in primary CD138+ myeloma cells (N=17) compared to normal plasma cells (NPC) (N=5). Whereas none of the NPCs expressed IL-17A, it was significantly over-expressed in majority of MM cells. In addition, these data also showed that the expression of other IL-17 family members (IL-7B, C, D, E & F) and Th17-associated pro-inflammatory cytokines (IL-21, IL-22 & IL-23) were not significantly elevated in primary myeloma cells compared to normal donor plasma cells. We further validated these observations by IL-17 immunoblot showing IL17 expression in all MM cell lines and 10 out of 14 primary patient MM cells; confirmed IL-17 expression in MM cells by quantitative RT-PCR, and flow cytometry and by immuno-histochemistry and confocal microscopy. We observed that IL-17 knock down by IL-17-specific siRNA inhibited MM cell growth as well as their ability to induce IL-6 production in co-cultures with BMSC. Finally, expression profile data from 172 uniformly treated patients showed that patients with lower IL-17A expression had superior overall survival compared to those with higher expression. These data confirms that MM cells express IL-17 and targeting it with a mAb will abrogate the autocrine loop making it an attractive therapeutic target. Disclosures: No relevant conflicts of interest to declare.
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Hurst, Stephen D., Tony Muchamuel, Daniel M. Gorman, Jonathan M. Gilbert, Theresa Clifford, Sylvia Kwan, Satish Menon, et al. "New IL-17 Family Members Promote Th1 or Th2 Responses in the Lung: In Vivo Function of the Novel Cytokine IL-25." Journal of Immunology 169, no. 1 (July 1, 2002): 443–53. http://dx.doi.org/10.4049/jimmunol.169.1.443.
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Wang, Xing, Hannah Kaiser, Amanda Kvist-Hansen, Benjamin D. McCauley, Lone Skov, Peter Riis Hansen, and Christine Becker. "IL-17 Pathway Members as Potential Biomarkers of Effective Systemic Treatment and Cardiovascular Disease in Patients with Moderate-to-Severe Psoriasis." International Journal of Molecular Sciences 23, no. 1 (January 5, 2022): 555. http://dx.doi.org/10.3390/ijms23010555.
Повний текст джерелаАнотація:
Psoriasis is a chronic inflammatory condition associated with atherosclerotic cardiovascular disease (CVD). Systemic anti-psoriatic treatments mainly include methotrexate and biological therapies targeting TNF, IL-12/23 and IL-17A. We profiled plasma proteins from patients with moderate-to-severe psoriasis to explore potential biomarkers of effective systemic treatment and their relationship to CVD. We found that systemically well-treated patients (PASI < 3.0, n = 36) had lower circulating levels of IL-17 pathway proteins compared to untreated patients (PASI > 10, n = 23). Notably, IL-17C and PI3 were decreased with all four examined systemic treatment types. Furthermore, in patients without CVD, we observed strong correlations among IL-17C/PI3/PASI (r ≥ 0.82, p ≤ 1.5 × 10−12) pairs or between IL-17A/PASI (r = 0.72, p = 9.3 × 10−8). In patients with CVD, the IL-17A/PASI correlation was abolished (r = 0.2, p = 0.24) and the other correlations were decreased, e.g., IL-17C/PI3 (r = 0.61, p = 4.5 × 10−5). Patients with moderate-to-severe psoriasis and CVD had lower levels of IL-17A compared to those without CVD (normalized protein expression [NPX] 2.02 vs. 2.55, p = 0.013), and lower IL-17A levels (NPX < 2.3) were associated with higher incidence of CVD (OR = 24.5, p = 0.0028, 95% CI 2.1–1425.1). As a result, in patients with moderate-to-severe psoriasis, we propose circulating IL-17C and PI3 as potential biomarkers of effective systemic anti-psoriatic treatment, and IL-17A as potential marker of CVD.
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Mammen, Manoj J., Jamil Ali, Amita Aurora, Umesh C. Sharma, Ravikumar Aalinkeel, Supriya D. Mahajan, Mark Sands, and Stanley A. Schwartz. "IL-17 Is a Key Regulator of Mucin-Galectin-3 Interactions in Asthma." International Journal of Cell Biology 2021 (June 9, 2021): 1–11. http://dx.doi.org/10.1155/2021/9997625.
Повний текст джерелаАнотація:
Mucus hypersecretion and chronic airway inflammation are standard characteristics of several airway diseases, such as chronic obstructive pulmonary disease and asthma. Increased mucus secretion from increased mucin gene expression in the airway epithelium is associated with poor prognosis and mortality. We previously showed that the absence of tissue inhibitor of metalloproteinase 1 (TIMP-1) enhances lung inflammation, airway hyperreactivity, and lung remodeling in asthma in an ovalbumin (OVA) asthma model of TIMP-1 knockout (TIMPKO) mice as compared to wild-type (WT) controls and mediated by increased galectin-3 (Gal-3) levels. Additionally, we have shown that in the lung epithelial cell line A549, Gal-3 inhibition increases interleukin-17 (IL-17) levels, leading to increased mucin expression in the airway epithelium. Therefore, in the current study, we further examined the relationship between Gal-3 and the production of IL-17-axis cytokines and critical members of the mucin family in the murine TIMPKO asthma model and the lung epithelium cell line A549. While Gal-3 may regulate a Th1/Th2 response, IL-17 could stimulate the mucin genes, MUC5B and MUC5AC. Gal-3 and IL-17 interactions induce mucus expression in OVA-sensitized mice. We conclude that Gal-3 may play an essential role in the pathogenesis of asthma, and modulation of Gal-3 may prove helpful in the treatment of this disease.
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Muhr, P., J. Zeitvogel, I. Heitland, T. Werfel, and M. Wittmann. "Expression of interleukin (IL)-1 family members upon stimulation with IL-17 differs in keratinocytes derived from patients with psoriasis and healthy donors." British Journal of Dermatology 165, no. 1 (June 24, 2011): 189–93. http://dx.doi.org/10.1111/j.1365-2133.2011.10302.x.
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Rajagopalan, Govindarajan, Ashton Krogman та Vaidehi Chowdhary. "Dissecting the pathogenic versus protective roles of IFN-γ and IL-17 in staphylococcal toxic shock syndrome and pneumonia using gene targeted HLA-DR3 transgenic mice". Journal of Immunology 200, № 1_Supplement (1 травня 2018): 117.3. http://dx.doi.org/10.4049/jimmunol.200.supp.117.3.
Повний текст джерелаАнотація:
Abstract The classical, adaptive T cell response to infectious agents is delayed and is antigen-specific. However, the superantigen (SAg) family of exotoxins, which are readily produced in vivo during Staphylococcus aureus infections, cause an immediate and non-specific activation of T cells, resulting in systemic elevation in many cytokines including IFN-γ and IL-17. While both IFN-γ and IL-17 are pro-inflammatory, they play distinct roles in mediating tissue injury and in immunity to infections. Therefore, to precisely delineate the roles of IFN-γ and IL-17 in immunopathology and immunity to diseases caused by S. aureus and its SAg, we first assessed the expression profiles of IFN-γ, IL-17 family members and their receptors in the spleens of HLA-DR3 transgenic mice challenged with a purified SAg using Illumina microarrays. The expression of ifng gene in spleens of HLA-DR3 transgenic mice was significantly higher than Il17a, Il17d and IL17f at all time-points tested (3, 6, 9, 24, 48 and 72 hrs, 3–4 mice per time point). Serum levels of these cytokines correlated with the gene expression data. Subsequently, HLA-DR3, HLA-DR3.IFN-γ−/− and HLA-DR3.IL-17−/− mice were generated and challenged with purified SAg or infected intratracheally with a SAg-producing strain of S. aureus. While both HLA-DR3 (mortality - 11/19) and HLA-DR3.IL-17−/− (mortality - 15/21) mice succumbed to SAg-induced toxic shock syndrome as well as pneumonia, HLA-DR.IFN-γ−/− mice (mortality - 1/11) were significantly protected (p<0.01) in both disease models. Bacterial loads were not different. In conclusion, our novel study using gene targeted humanized mice reveals that while both Th1 and Th17 cells are robustly activated by SAg, Th1 cells and IFN-γ play a lethal role.
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Wang, Jinghua, Guoping Wu, Brian Manick, Vida Hernandez, Mark Renelt, Ming Bi, Jun Li, and Vassilios Kalabokis. "VSIG-3/IGSF11 is a ligand of VISTA/PD-1H and inhibits human T cell function." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 154.1. http://dx.doi.org/10.4049/jimmunol.198.supp.154.1.
Повний текст джерелаАнотація:
Abstract B7 family members and their receptors play a central role in the regulation of T cell responses through T cell costimulation and coinhibition pathways that constitute very attractive targets for the development of immunotherapeutic drugs. In this study, we report that VSIG-3/IGSF11 is a ligand of B7 family member VISTA/PD-1H and inhibits human T cell functions through a novel VSIG-3/VISTA pathway. Extensive functional ELISA binding screening assay reveals that VSIG-3 does bind the new B7 family member VISTA, but does not interact with other known members of the B7 family. Furthermore, VSIG-3 inhibits human T cell proliferation in the presence of T cell receptor signaling. In addition, VSIG-3 significantly reduces cytokine and chemokine production by human T cells including IFN-γ, IL-2, IL-17, CCL5/Rantes, CCL3/MIP-1alpha, and CXCL11/I-TAC. Anti-VISTA neutralization antibodies attenuate the binding of VSIG-3 and VISTA, as well as VSIG-3 induced T cell inhibition. Thus, we have identified a novel B7 pathway that is able to inhibit human T cell proliferation and cytokine production. This unique VSIG-3/VISTA coinhibitory pathway may provide new strategies for the treatment of human cancers, autoimmune disorders, infection, and transplant rejection and may help to design better vaccines.
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Brown, Rachel Anne, Andrew W. Dangel, Ankita Saini, and Eugene M. Oltz. "Regulators of Type III Cytokines in Type III Innate lymphoid Cells Identified by CRISPR Activation and Inhibition Screens." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 106.04. http://dx.doi.org/10.4049/jimmunol.206.supp.106.04.
Повний текст джерелаАнотація:
Abstract Type III cytokines interleukin (IL)-22 and IL-17 are expressed by both innate and adaptive immune cells to defend against extracellular pathogens, yet their dysregulation contributes to autoimmunity and malignancy. A deeper knowledge of IL-22/17 regulation is warranted to understand physiologic processes as well as disease pathogenesis, thereby elucidating druggable targets. Toward this goal, we applied genome-wide CRISPR activation (CRISPRa) and CRISPR inhibition (CRISPRi) screens to identify the collection of factors that positively or negatively regulate IL-17/22 expression in a murine type III innate lymphoid cell (ILC3) model. Following lentiviral transduction of a CRISPRi or CRISPRa guide RNA (gRNA) library, cells were stimulated and sorted by levels of intracellular IL-22/17 protein expression. Relative gRNA frequencies in each sequenced population revealed enrichment and depletion of potential regulators (“hits”), which were then tested with gene-specific gRNAs to validate or exclude them from further study. These genome-wide screens have illuminated hits from several biological pathways, ranging from transmembrane channels to RNA splicing. We identify previously known regulators, including IL23R, STAT3, and ZFP36, as well as novel potential regulators, including SLC family members and a nuclear protein called SON. Our screens provide a diverse array of candidate factors that govern expression of type III cytokines by ILC3s, with potential for extrapolation to other cytokine-expressing cells. Genome-wide gain and loss of function screens are powerful, complementary tools to facilitate regulatory pathway discovery.
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Remedios, Kelly A., Bahar Zirak, Priscila Munoz Sandoval, Margaret M. Lowe, Devi Boda, Evan Henley, Shrishti Bhattrai, et al. "The TNFRSF members CD27 and OX40 coordinately limit TH17 differentiation in regulatory T cells." Science Immunology 3, no. 30 (December 21, 2018): eaau2042. http://dx.doi.org/10.1126/sciimmunol.aau2042.
Повний текст джерелаАнотація:
Regulatory T cells (Tregs) are closely related to TH17 cells and use aspects of the TH17-differentiation program for optimal immune regulation. In several chronic inflammatory human diseases, Tregs express IL-17A, suggesting that dysregulation of TH17-associated pathways in Tregs may result in either loss of suppressive function and/or conversion into pathogenic cells. The pathways that regulate the TH17 program in Tregs are poorly understood. We have identified two TNF receptor superfamily (TNFRSF) members, CD27 and OX40, that are preferentially expressed by skin-resident Tregs. Both CD27 and OX40 signaling suppressed the expression of TH17-associated genes from Tregs in a cell-intrinsic manner in vitro and in vivo. However, only OX40 played a nonredundant role in promoting Treg accumulation. Tregs that lacked both CD27 and OX40 were defective in controlling skin inflammation and expressed high levels of IL-17A, as well as the master TH17 transcription factor, RORγt. Last, we found that CD27 expression was inversely correlated with Treg IL-17 production in skin of patients with psoriasis and hidradenitis suppurativa. Together, our results suggest that TNFRSF members play both redundant and distinct roles in regulating Treg plasticity in tissues.
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Koike, Yuta, Sayaka Kuwatsuka, Katsutaro Nishimoto, Daisuke Motooka, and Hiroyuki Murota. "Skin Mycobiome of Psoriasis Patients is Retained during Treatment with TNF and IL-17 Inhibitors." International Journal of Molecular Sciences 21, no. 11 (May 29, 2020): 3892. http://dx.doi.org/10.3390/ijms21113892.
Повний текст джерелаАнотація:
Background: Biological treatment relieves refractory skin lesions in patients with psoriasis; however, changes in the fungal microbiome (the mycobiome) on the skin are unclear. Methods: The skin mycobiome of psoriasis patients treated with TNF inhibitors (TNFi, n = 5) and IL-17 inhibitors (IL-17i, n = 7) was compared with that of patients not receiving systemic therapy (n = 7). Skin swab samples were collected from non-lesional post-auricular areas. Fungal DNA was sequenced by ITS1 metagenomic analysis and taxonomic classification was performed. Results: An average of 37543 reads/sample were analyzed and fungi belonging to 31 genera were detected. The genus Malassezia accounted for >90% of reads in 7/7 samples from the no-therapy group, 4/5 from the TNFi group, and 5/7 from the IL-17i group. Biodiversity was low in those three groups. Few members of the genus trichophyton were detected; the genus Candida was not detected at all. Among the Malassezia species, M. restricta was the major species in 6/7 samples from the no-therapy group, 4/5 from the TNFi group, and 5/7 from the IL-17i group whose the other largest species revealed M. globosa. Conclusions: The mycobiome is retained on post-auricular skin during systemic treatment with TNF and IL-17 inhibitors.
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Yokota, K., K. Ariizumi, T. Kitajima, P. R. Bergstresser, N. E. Street, and A. Takashima. "Cytokine-mediated communication between dendritic epidermal T cells and Langerhans cells. In vitro studies using cell lines." Journal of Immunology 157, no. 4 (August 15, 1996): 1529–37. http://dx.doi.org/10.4049/jimmunol.157.4.1529.
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Abstract Murine epidermis contains two leukocyte populations: Langerhans cells (LC), which are APC of dendritic cell (DC) lineage, and dendritic epidermal T cells (DETC), which are members of the tissue-type gamma delta T cell family. Despite close physical approximation in vivo, the extent to which LC and DETC affect each other's function has remained unknown. We addressed this question using the long term DC line XS52 and the gamma delta T cell line 7-17, both of which were established from mouse epidermis, and both of which retain important features of the resident populations from which they were derived. XS52 DC proliferated maximally when cocultured with gamma-irradiated 7-17 DETC. They also proliferated in response to culture supernatants collected from anti-CD3- or Con A-activated 7-17 DETC, but not from nonstimulated DETC. In both systems, DETC-induced XS52 DC growth was inhibited partially (up to 70%) by Abs against granulocyte/macrophage CSF (GM-CSF) or CD115 (CSF-1 receptor) and nearly completely (up to 90%) by both together. Among 28 tested cytokines, only GM-CSF, CSF-1, IL-4, and IL-13 promoted XS52 DC growth significantly. Anti-IL-4 failed to inhibit DETC-induced XS52 cell growth, and IL-4 was not detectable in DETC supernatants. Thus, we conclude that GM-CSF and CSF-1 (and perhaps IL-13) account for the DC growth-promoting activity secreted by DETC. These results suggest that during coculture, XS52 DC activate 7-17 DETC to secrete both GM-CSF and CSF-1. In fact, when cultured with XS52 DC, 7-17 DETC also elevated their expression of the gamma c receptor and acquired proliferative responsiveness to their own growth factor IL-15. We propose that LC and DETC in situ may interact with each other in a similar manner, thereby regulating their residence and function.
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Kölliker Frers, Rodolfo, Matilde Otero-Losada, Tamara Kobiec, María Inés Herrera, Lucas Udovin, Carlos F. Kusnier, and Francisco Capani. "Interleukin-1 Links Autoimmune and Autoinflammatory Pathophysiology in Mixed-Pattern Psoriasis." Mediators of Inflammation 2021 (October 16, 2021): 1–9. http://dx.doi.org/10.1155/2021/2503378.
Повний текст джерелаАнотація:
Autoinflammatory and autoimmune diseases are characterized by an oversensitive immune system with loss of the physiological endogenous regulation, involving multifactorial self-reactive pathological mechanisms of mono- or polygenic nature. Failure in regulatory mechanisms triggers a complex network of dynamic relationships between innate and adaptive immunity, leading to coexistent autoinflammatory and autoimmune processes. Sustained exposure to a trigger or a genetic alteration at the level of the receptors of the natural immune system may lead to abnormal activation of the innate immune system, adaptive system activation, loss of self-tolerance, and systemic inflammation. The IL-1 family members critically activate and regulate innate and adaptive immune responses’ diversity and plasticity in autoimmune and/or autoinflammatory conditions. The IL-23/IL-17 axis is key in the communication between innate immunity (IL-23-producing myeloid cells) and adaptive immunity (Th17- and IL-17-expressing CD8+ T cells). In psoriasis, these cytokines are decisive to the different clinical presentations, whether as plaque psoriasis (psoriasis vulgaris), generalized pustular psoriasis (pustular psoriasis), or mixed forms. These forms reflect a gradient between autoimmune pathophysiology with predominant adaptive immune response and autoinflammatory pathophysiology with predominant innate immune response.
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Jung, Christian, Norbert Gerdes, Michael Fritzenwanger, and Hans Reiner Figulla. "Circulating Levels of Interleukin-1 Family Cytokines in Overweight Adolescents." Mediators of Inflammation 2010 (2010): 1–6. http://dx.doi.org/10.1155/2010/958403.
Повний текст джерелаАнотація:
Objectives. Obesity and related diseases are dramatically increasing problems, particularly in children and adolescents. We determined circulating levels of different interleukin (IL)-1 family members in normal weight and overweight adolescents.Methods. Seventy male, Caucasian adolescents (13–17 years) were recruited. Thirty-five had a body-mass index (BMI) above the 90th age-specific percentile. IL-1α, IL-1β, IL-1 receptor antagonist (IL-1ra), and IL-18 were determined using multiplex-technology.Results. IL-18 concentrations were higher in the overweight group compared to normal weight (161.6±40.7 pg/ml versus134.7±43.4 pg/ml,P=.009). Concentrations of circulating IL-1βlevels were below the detection threshold. IL-18 (R2:0.355,P<.01) and IL-1ra (R2:0.287,P<.05) correlated with BMI, whereas IL-1αdid not.Conclusions. Accumulating data indicate the importance of the endocrine function of adipose tissue for the pathophysiological consequences of obesity-related co-morbidities. Since IL-18 is involved in the pathogenesis of different cardiovascular diseases, we conclude that IL-18 may represent a link between obesity and related co-morbidities in children and adolescents.
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Marquet, Sandrine, Ianina Conte, Belco Poudiougou, Laurent Argiro, Sandrine Cabantous, Hélia Dessein, Florence Burté, et al. "TheIL17FandIL17RAGenetic Variants Increase Risk of Cerebral Malaria in Two African Populations." Infection and Immunity 84, no. 2 (December 14, 2015): 590–97. http://dx.doi.org/10.1128/iai.00671-15.
Повний текст джерелаАнотація:
Cerebral malaria (CM) is a neurological complication of infection withPlasmodium falciparumthat is partly caused by cytokine-mediated inflammation. It is not known whether interleukin-17 (IL-17) cytokines, which regulate inflammation, control the development of CM. To evaluate the involvement of IL-17 cytokines in CM, we analyzed 46 common polymorphisms inIL17A,IL17F, andIL17RA(which encodes the common receptor chain of the members of the IL-17 family) in two independent African populations. A case-control study involving 115 Nigerian children with CM and 160 controls from the community (CC) showed thatIL17Freference single nucleotide polymorphism (SNP) 6913472 (rs6913472) (P= 0.004; odds ratio [OR] = 3.12),IL17Frs4715291 (P= 0.004; OR = 2.82),IL17RArs12159217 (P= 0.01; OR = 2.27), andIL17RArs41396547 (P= 0.026; OR = 3.15) were independently associated with CM. A replication study was performed in 240 nuclear Malian family trios (two parents with one CM child). We replicated the association for 3 SNPs,IL17Frs6913472 (P= 0.03; OR = 1.39),IL17RArs12159217 (P= 0.01; OR = 1.52), andIL17RArs41396547 (P= 0.04; OR = 3.50). We also found that one additional SNP,IL17RArs41433045, in linkage disequilibrium (LD) with rs41396547, was associated with CM in both Nigeria and Mali (P= 0.002; OR = 4.12 in the combined sample). We excluded the possibility that SNPs outsideIL17FandIL17RA, in strong LD with the associated SNPs, could account for the observed associations. Furthermore, the results of a functional study indicated that the aggravating GA genotype ofIL17Frs6913472 was associated with lower IL-17F concentrations. Our findings show for the first time thatIL17FandIL17RApolymorphisms modulate susceptibility to CM and provide evidence that IL-17F protects against CM.
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Espinosa, Alexander, Valerie Dardalhon, Susanna Brauner, Aurelie Ambrosi, Rowan Higgs, Fransisco J. Quintana, Maria Sjöstrand, et al. "Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23–Th17 pathway." Journal of Experimental Medicine 206, no. 8 (July 27, 2009): 1661–71. http://dx.doi.org/10.1084/jem.20090585.
Повний текст джерелаАнотація:
Ro52/Trim21 is targeted as an autoantigen in systemic lupus erythematosus and Sjögren's syndrome. Polymorphisms in the Ro52 gene have been linked to these autoimmune conditions, but the molecular mechanism by which Ro52 may promote development of systemic autoimmune diseases has not been explored. To address this issue, we generated Ro52-null mice (Ro52−/−), which appear phenotypically normal if left unmanipulated. However, Ro52−/− mice develop severe dermatitis extending from the site of tissue injury induced by ear tags. The affected mice further develop several signs of systemic lupus with hypergammaglobulinemia, autoantibodies to DNA, proteinuria, and kidney pathology. Ro52, which was recently identified as an E3 ligase, mediates ubiquitination of several members of the interferon regulatory factor (IRF) family, and the Ro52-deficient mice have an enhanced production of proinflammatory cytokines that are regulated by the IRF transcription factors, including cytokines involved in the Th17 pathway (interleukin [IL] 6, IL-12/IL-23p40, and IL-17). Loss of IL-23/IL-17 by genetic deletion of IL-23/p19 in the Ro52−/− mice conferred protection from skin disease and systemic autoimmunity. These data reveal that the lupus-associated Ro52 protein is an important negative regulator of proinflammatory cytokine production, and they provide a mechanism by which a defective Ro52 function can lead to tissue inflammation and systemic autoimmunity through the IL-23–Th17 pathway.
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Zhou, Xiaohui, Jiayou Tang, Jie Liu, Qingshu Meng, Zhongmin Liu, and Huimin Fan. "IL-25 promotes the function of CD4+CD25+ T regulatory cells and prolongs skin-graft survival in murine models (IRC5P.620)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 58.3. http://dx.doi.org/10.4049/jimmunol.194.supp.58.3.
Повний текст джерелаАнотація:
Abstract Interleukin (IL)-25, also known as Interleukin (IL)-17E, belonging to the IL-17 family. Unlike the other members, IL-25 has long been deemed as a pro-inflammatory cytokine favoring Th2--type immune response. Here, we show that expression of IL-25 in skin and subcutaneous tissues were constantly, while increased during allograft rejection. At same time, deficiency of IL-25 aggravates skin allograft rejection in murine models. Further experiments showed deficiency of IL-25 down-regulated the expression of Foxp3 among CD4+ cells and aggravated skin allograft rejections in murine models. While, exogenous IL-25 restored the Foxp3 expression and the function of Tregs in vitro. Adoptively transfer of IL-25 deficient Tregs failed to protect the allograft from rejection, compared to the WT Tregs. Moreover, IL-25 promoted phosphorylation of NFAT2, up-regulated the Foxp3 expression and contributed to the function of Tregs. Our findings indicate that IL-25 can promote the function of Tregs via impeding the interaction of NFAT2 and Foxp3, and prolong skin-graft survival.
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Shaikh, Sadiya Bi, Ashwini Prabhu, and Yashodhar Prabhakar Bhandary. "Interleukin-17A: A Potential Therapeutic Target in Chronic Lung Diseases." Endocrine, Metabolic & Immune Disorders - Drug Targets 19, no. 7 (October 11, 2019): 921–28. http://dx.doi.org/10.2174/1871530319666190116115226.
Повний текст джерелаАнотація:
Background: Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has gained a lot of attention because of its involvement in respiratory diseases. Interleukin-17 cytokine family includes six members, out of which, IL-17A participates towards the immune responses in allergy and inflammation. It also modulates the progression of respiratory disorders. Objective: The present review is an insight into the involvement and contributions of the proinflammatory cytokine IL-17A in chronic respiratory diseases like Idiopathic Pulmonary Fibrosis (IPF), Chronic Obstructive Pulmonary Distress (COPD), asthma, pneumonia, obliterative bronchiolitis, lung cancer and many others. Conclusion: IL-17A is a major regulator of inflammatory responses. In all the mentioned diseases, IL- 17A plays a prime role in inducing the diseases, whereas the lack of this pro-inflammatory cytokine reduces the severity of respective respiratory diseases. Thereby, this review suggests IL-17A as an instrumental target in chronic respiratory diseases.
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Vigne, Solenne, Gaby Palmer, Céline Lamacchia, Praxedis Martin, Dominique Talabot-Ayer, Emiliana Rodriguez, Francesca Ronchi, et al. "IL-36R ligands are potent regulators of dendritic and T cells." Blood 118, no. 22 (November 24, 2011): 5813–23. http://dx.doi.org/10.1182/blood-2011-05-356873.
Повний текст джерелаАнотація:
Abstract IL-36α (IL-1F6), IL-36β (IL-1F8), and IL-36γ (IL-1F9) are members of the IL-1 family of cytokines. These cytokines bind to IL-36R (IL-1Rrp2) and IL-1RAcP, activating similar intracellular signals as IL-1, whereas IL-36Ra (IL-1F5) acts as an IL-36R antagonist (IL-36Ra). In this study, we show that both murine bone marrow-derived dendritic cells (BMDCs) and CD4+ T lymphocytes constitutively express IL-36R and respond to IL-36α, IL-36β, and IL-36γ. IL-36 induced the production of proinflammatory cytokines, including IL-12, IL-1β, IL-6, TNF-α, and IL-23 by BMDCs with a more potent stimulatory effect than that of other IL-1 cytokines. In addition, IL-36β enhanced the expression of CD80, CD86, and MHC class II by BMDCs. IL-36 also induced the production of IFN-γ, IL-4, and IL-17 by CD4+ T cells and cultured splenocytes. These stimulatory effects were antagonized by IL-36Ra when used in 100- to 1000-fold molar excess. The immunization of mice with IL-36β significantly and specifically promoted Th1 responses. Our data thus indicate a critical role of IL-36R ligands in the interface between innate and adaptive immunity, leading to the stimulation of T helper responses.
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Fu, Yongyao, Byunghee koh, Benjamin J. Ulrich, Rakshin Kharwadkar, and Mark H. Kaplan. "BATF-interacting proteins dictate specificity in Th subset activity." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 128.14. http://dx.doi.org/10.4049/jimmunol.202.supp.128.14.
Повний текст джерелаАнотація:
Abstract The basic leucine zipper transcription factor BATF is expressed in multiple Th subsets and cooperates with other factors to regulate gene transcription. BATF activates lineage-specific cytokines in Th subsets, activating IL-9 in Th9 cells and IL-17 in Th17 cells. The mechanism for this restricted activity is unclear. In this report we define BATF binding partners that contribute to Th subset-specific functions. Although BATF and IRF4 are expressed in greater amounts in Th9 than Th17, increased expression of both factors is not sufficient to induce IL-9 in Th17 cells. BATF also requires heterodimer formation with Jun family members to bind DNA and induce gene expression. We observed that JunB and c-Jun, but not JunD, promote IL-9 production in Th9 cells. Ectopic expression of BATF with either JunB or c-Jun generates modest but significant increases in IL-9 production in Th17 cells, suggesting that the low expression of Jun family members is one factor limiting the ability of BATF to induce IL-9 in Th17 cells. We further identified that Bach2 positively regulates IL-9 production by directly binding to the Il9 gene and by increasing transcription factor expression in Th9 cells. Strikingly, co-transduction of Bach2 and BATF significantly induces IL-9 production in both Th9 and Th17 cell. Taken together, our results reveal that JunB, c-Jun and Bach2 cooperate with BATF to contribute to the specificity of BATF-dependent cytokine induction in Th subsets.
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Wright, Jill F., Frann Bennett, Bilian Li, Jonathan Brooks, Deborah P. Luxenberg, Matthew J. Whitters, Kathleen N. Tomkinson, et al. "The functional activity of human IL-17A, IL-17F and IL-17A/IL-17F cytokines is dependent on the receptors IL-17R and IL-17RC (94.31)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S176. http://dx.doi.org/10.4049/jimmunol.178.supp.94.31.
Повний текст джерелаАнотація:
Abstract IL-17A and IL-17F are members of the IL-17 cytokine family and have been detected in tissue samples from patients with autoimmune disease. Recent data has shown that these cytokines are secreted by a new CD4+ T cell lineage known as Th17 cells. We have recently demonstrated that activated human CD4+ T cells also produce the IL-17A/IL-17F heterodimer with in vitro functional activity. Both IL-17R and IL-17RC are required for activity of IL-17A and IL-17F. However, the question remains whether IL-17A/IL-17F also utilizes the same receptors for activity or whether it signals through different receptor chains. ELISA and BiaCore-based binding experiments were performed to determine if IL-17A/IL-17F could bind to IL-17R and IL-17RC. We find that IL-17A, IL-17F and IL-17A/IL-17F each bind to IL-17R but with different affinities, whereas they bind to IL-17RC with comparable affinity. Using cell based assays, we have evaluated the functional activity of IL-17A, IL-17F and IL-17A/IL-17F in the presence of soluble receptors, antibodies to the receptors and IL-17R and IL-17RC siRNA. We find that the activity of IL-17A, IL-17F and IL-17A/IL-17F is decreased when the expression of IL-17R is reduced, whereas the activity of the cytokines decreases to a lesser extent when the expression of IL-17RC is reduced. In conclusion, our results suggest that IL-17A, IL-17F and IL-17A/IL-17F each bind and signal through the same receptor complex.
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Kim, Mee Rhan, Raffi Manoukian, Richard Yeh, Scott M. Silbiger, Dimitry M. Danilenko, Sheila Scully, Jilin Sun, et al. "Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production." Blood 100, no. 7 (October 1, 2002): 2330–40. http://dx.doi.org/10.1182/blood-2002-01-0012.
Повний текст джерелаАнотація:
We have identified and cloned a novel human cytokine with homology to cytokines of the interleukin-17 (IL-17) family, which we have termed human IL-17E (hIL-17E). With the identification of several IL-17 family members, it is critical to understand the in vivo function of these molecules. We have generated transgenic mice overexpressing hIL-17E using an apolipoprotein E (ApoE) hepatic promoter. These mice displayed changes in the peripheral blood, particularly, a 3-fold increase in total leukocytes consisting of increases in eosinophils, lymphocytes, and neutrophils. Splenomegaly and lymphoadenopathy were predominant and included marked eosinophil infiltrates and lymphoid hyperplasia. CCR3+ eosinophils increased in the blood and lymph nodes of the transgenic mice by 50- and 300-fold, respectively. Eosinophils also increased 8- to 18-fold in the bone marrow and spleen, respectively. In the bone marrow, most of the eosinophils had an immature appearance. CD19+ B cells increased 2- to 5-fold in the peripheral blood, 2-fold in the spleen, and 10-fold in the lymph nodes of transgenic mice, whereas CD4+ T lymphocytes increased 2-fold in both blood and spleen. High serum levels of the cytokines IL-2, IL-4, IL-5, granulocyte colony-stimulating factor, eotaxin, and interferon γ were observed. Consistent with B-lymphocyte increases, serum immunoglobulin (Ig) M, IgG, and IgE were significantly elevated. Antigenic challenge of the transgenic mice with keyhole limpet hemocyanin (KLH) resulted in a decrease in anti-KLH IgG accompanied by increases of anti-KLH IgA and IgE. In situ hybridization of transgenic tissues revealed that IL-17Rh1 (IL-17BR/Evi27), a receptor that binds IL-17E, is up-regulated. Taken together, these data indicate that IL-17E regulates hematopoietic and immune functions, stimulating the development of eosinophils and B lymphocytes. The fact that hIL-17E overexpression results in high levels of circulating eosinophils, IL-4, IL-5, eotaxin, and IgE suggests that IL-17E may be a proinflammatory cytokine favoring Th2-type immune responses.
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Koh, Byunghee, and Mark H. Kaplan. "Etv5 promotes IL-10 production in Th2 cells." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 58.15. http://dx.doi.org/10.4049/jimmunol.196.supp.58.15.
Повний текст джерелаАнотація:
Abstract The anti-inflammatory cytokine, IL-10, suppresses inflammatory responses at mucosal surfaces. Among T helper cell subsets, Th2 cells produce the highest concentrations. However, the transcription factors that regulate Il10 gene expression have not been completely defined. Etv5 is a member of the ETS transcription factor family that promotes production of IL-17 in Th17 cells and IL-9 in Th9 cells. To define the effects of Etv5 deficiency on cytokine expression in Th2 cells, T cells from CD4 specific Etv5 knockout (Etv5fl/flCD4-Cre+, termed Etv5 KO below) and littermate control (Etv5fl/fl CD4-Cre-, termed WT below) mice were differentiated under Th2 conditions. Etv5 was required for maximal IL-10 production and modestly repressed the Th2 cytokines IL-4, IL-5 and IL-13. In mice sensitized with Aspergilus fumigatus extract, IL-10 production in both BAL and lung was significantly reduced in Etv5 KO mice, consistent with in vitro data. Using ChIP and reporter assays, we showed that Etv5 directly binds to the Il10 locus, specifically at the CNS3 region. Etv5 promotes IL-10 production by recruiting IL-10 inducing transcription factors including Jun family members, IRF4 and E4BP4, and the binding of these factors to the Il10 locus, but not the expression of these factors, was decreased in the absence of Etv5. Ectopic GATA3 and E4BP4 expression recovers IL-10 production to wild type amounts, suggesting that Etv5 enhances the efficiency of function of these factors. Importantly, ectopic Etv5 expression in Etv5 KO Th2 cells restored binding of the factors to the Il10 locus. Thus, Etv5 promotes IL-10 production by enhancing the recruitment of IL-10 inducing transcription factors.
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Monteiro, Mabelle Freitas, Hélvis Enri de Sousa Paz, Larissa Bizarre, Gabriela Martin Bonilha, Marcio Zaffalon Casati, and Renato Corrêa Viana Casarin. "Salivary IL-4: A Bleeding Predictor on Probing in Descendants of Severe Periodontitis Patients." Journal of Clinical Pediatric Dentistry 46, no. 2 (March 1, 2022): 132–36. http://dx.doi.org/10.17796/1053-4625-46.2.7.
Повний текст джерелаАнотація:
Objective: Periodontitis in younger patients can cause severe periodontal destruction, and cases are usually more numerous in members of the same family due to the sharing of susceptibility factors. Thus, the use of a familial study design could improve our understanding of initial alterations in periodontal tissue. This observational study aimed to evaluate the salivary inflammatory pattern in descendants of periodontitis patients and identify any correlation with the clinical periodontal condition. Study design: Fifteen children of Generalized Aggressive Periodontitis (GAgP) patients and 15 children with periodontally healthy parents were evaluated for their plaque index (PI), gingival index (GI), bleeding on probing (BoP), and probing depth (PD). The concentrations of interferon (IFN)-γ, interleukin (IL)-10, IL-17, IL-1β, IL-4, and tumor necrosis factor (TNF)-α were measured in unstimulated saliva using the Luminex MAGPix platform. Results: Children from the GAgP group presented higher probing depth (PD) and bleeding on probing (BoP) (p<0.05) and lower release of IL-4 in saliva (p<0.05) than the periodontally healthy group. The cytokines IL-10, IFN-γ, IL-17, and IL-4 were negatively correlated with the gingival index, while IL-4 was negatively correlated with BoP. A regression analysis revealed that salivary IL-4 and plaque were predictors of BoP. Conclusions: Children of GAgP parents presented lower salivary IL-4 and higher BoP and PD than children from periodontally healthy families. Additionally, salivary IL-4 was a predictor of bleeding on probing in the children, suggesting that the lower presence of this anti-inflammatory cytokine is related to higher clinical inflammation.