IL-17 family: cytokines, receptors and signaling.
TL;DR: The proximal adaptor Act1 is a common mediator during the signaling of all IL-17 cytokines so far and is thus involved inIL-17 mediated host defense and IL- 17-driven autoimmune conditions.
About: This article is published in Cytokine.The article was published on 2013-11-01 and is currently open access. It has received 441 citations till now. The article focuses on the topics: IL 17 family & Janus kinase 1.
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TL;DR: Whether Th cell pathogenicity can be defined solely based on their cytokine profiles and whether rigid definition of a Th cell subset by its cytokine profile is helpful are discussed.
792 citations
TL;DR: Therapeutic interventions to reduce activation of cells of both the innate and adaptive immune system may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.
Abstract: For >50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, deoxycorticosterone acetate-salt, and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including interleukin-17, interferon-γ, tumor necrosis factorα, and interleukin-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption, and increased renal fibrosis. Recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.
516 citations
Cites background from "IL-17 family: cytokines, receptors ..."
...In addition to CD4 T cells, γ/δ T cells, the T C 17 subset of CD8 T cells, some B cells and natural killer T cells, and miscellaneous other cells produce IL-17.(34) There are 6 isoforms of IL17, classified as A–F, which share varying degrees of sequence homology....
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...In ad- dition to CD4+ T cells, γ/δ T cells, the T C 17 subset of CD8+ T cells, some B cells and natural killer T cells, and miscellaneous other cells produce IL-17....
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...IL-17A has been implicated in a variety of autoimmune diseases, including psoriasis, experimental autoimmune encephalomyelitis, asthma, Crohn’s disease, and rheumatoid arthritis.(34) The anti-IL-17A antibodies, Ixekizumab and Secukinumab, as well as the anti-IL17RA receptor antibody, Brodalumab, have proven effective in phase II/III human trials for the treatment of psoriasis(38,39) and are being studied in other inflammatory diseases....
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...As mentioned earlier, IL-6 is a major signal to promote polarization of CD4+ T cells to produce IL-17....
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TL;DR: Major challenges for MS research involve understanding the mechanisms of disease progression, developing treatment for progressive MS, and determining the degree to which progressive disease can be prevented by early treatment.
504 citations
Cites background from "IL-17 family: cytokines, receptors ..."
...It is less clear how IL-17 mediates autoimmunity, as responses to IL-17 are pleiotropic and the receptors for IL-17 are ubiquitously expressed, with IL-17-induced responses differing depending upon cell type (Zhang et al., 2013; Gu et al., 2013)....
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TL;DR: This review discusses both the activators and the inhibitors of IL-17 signal transduction, and also the physiological implications of these events, and highlights the surprisingly diverse means by which these regulators control expression ofIL-17-dependent inflammatory genes, as well as the major target cells that respond to IL- 17 signaling.
423 citations
TL;DR: The data discussed in this review cumulatively indicate that innate-derived IL-17 constitutes a major element in the altered immune response against self antigens or the perpetuation of inflammation, particularly at mucosal sites.
301 citations
References
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TL;DR: The investigation of the differentiation, effector function, and regulation of Th17 cells has opened up a new framework for understanding T cell differentiation and now appreciate the importance of Th 17 cells in clearing pathogens during host defense reactions and in inducing tissue inflammation in autoimmune disease.
Abstract: CD4+ T cells, upon activation and expansion, develop into different T helper cell subsets with different cytokine profiles and distinct effector functions. Until recently, T cells were divided into Th1 or Th2 cells, depending on the cytokines they produce. A third subset of IL-17-producing effector T helper cells, called Th17 cells, has now been discovered and characterized. Here, we summarize the current information on the differentiation and effector functions of the Th17 lineage. Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors. Th17 cells also secrete IL-21 to communicate with the cells of the immune system. The differentiation factors (TGF-β plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the transcription factors (STAT3, RORγt, and RORα) involved in the development of Th17 cells have just been identified. The participation of TGF-β in the differentiation of Th17 cells places ...
4,548 citations
TL;DR: The authors showed that colonisation of mice with a segmented filamentous bacterium (SFB) is sufficient to induce the appearance of CD4+ T helper cells that produce IL-17 and IL-22 (Th17 cells) in the lamina propria.
3,860 citations
TL;DR: Large-scale analysis of transcripts in MS lesions elucidates new aspects of pathology and opens possibilities for therapy, and results in EAE corroborate the microarray studies on MS lesions.
Abstract: Microarray analysis of multiple sclerosis (MS) lesions obtained at autopsy revealed increased transcripts of genes encoding inflammatory cytokines, particularly interleukin-6 and -17, interferon-gamma and associated downstream pathways. Comparison of two poles of MS pathology--acute lesions with inflammation versus 'silent' lesions without inflammation--revealed differentially transcribed genes. Some products of these genes were chosen as targets for therapy of experimental autoimmune encephalomyelitis (EAE) in mice. Granulocyte colony-stimulating factor is upregulated in acute, but not in chronic, MS lesions, and the effect on ameliorating EAE is more pronounced in the acute phase, in contrast to knocking out the immunoglobulin Fc receptor common gamma chain where the effect is greatest on chronic disease. These results in EAE corroborate the microarray studies on MS lesions. Large-scale analysis of transcripts in MS lesions elucidates new aspects of pathology and opens possibilities for therapy.
1,676 citations
TL;DR: It is likely that IL-17 expression in IBD may be associated with altered immune and inflammatory responses in the intestinal mucosa and increased in patients with inflammatory bowel disease.
Abstract: Background and aim: Interleukin (IL) 17 is a cytokine which exerts strong proinflammatory activities. In this study we evaluated changes in IL-17 expression in the inflamed mucosa and in the serum of patients with inflammatory bowel disease (IBD).
Methods: Tissue samples were obtained endoscopically or surgically from patients with ulcerative colitis (UC) (n=20), Crohn’s disease (CD) (n=20), infectious colitis (n=5), ischaemic colitis (n=8), and normal colorectal tissues (n=15). IL-17 expression was evaluated by a standard immunohistochemical procedure. Serum IL-17 levels were determined by ELISA. IL-17 mRNA expression was analysed by reverse transcriptase-polymerase chain reaction.
Results: IL-17 expression was not detected in samples from normal colonic mucosa, infectious colitis, or ischaemic colitis. In the inflamed mucosa of active UC and CD patients, IL-17 expression was clearly detectable in CD3+ T cells or CD68+ monocytes/macrophages. The average number of IL-17+ cells was significantly increased in active UC and CD patients compared with inactive patients. IL-17 mRNA expression was not detected in normal mucosa but was detectable in the mucosa from active UC and CD patients. IL-17 was not detected in the sera from normal individuals, infectious colitis, or ischaemic colitis patients but IL-17 levels were significantly elevated in IBD patients.
Conclusions: IL-17 expression in the mucosa and serum was increased in IBD patients. It is likely that IL-17 expression in IBD may be associated with altered immune and inflammatory responses in the intestinal mucosa.
1,624 citations
TL;DR: The effector cytokines of Th17 cells mediate the crucial crosstalk between immune system and tissues, and play indispensable roles in tissue immunity.
1,608 citations