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The IL-17 Family of Cytokines in Health and Disease.

ABSTRACT: The interleukin 17 (IL-17) family of cytokines contains 6 structurally related cytokines, IL-17A through IL-17F. IL-17A, the prototypical member of this family, just passed the 25th anniversary of its discovery. Although less is known about IL-17B-F, IL-17A (commonly known as IL-17) has received much attention for its pro-inflammatory role in autoimmune disease. Over the past decade, however, it has become clear that the functions of IL-17 are far more nuanced than simply turning on inflammation. Accumulating evidence indicates that IL-17 has important context- and tissue-dependent roles in maintaining health during response to injury, physiological stress, and infection. Here, we discuss the functions of the IL-17 family, with a focus on the balance between the pathogenic and protective roles of IL-17 in cancer and autoimmune disease, including results of therapeutic blockade and novel aspects of IL-17 signal transduction regulation.

SUBMITTER: McGeachy MJ

PROVIDER: S-EPMC6474359 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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The IL-17 Family of Cytokines in Health and Disease.

McGeachy Mandy J MJ Cua Daniel J DJ Gaffen Sarah L SL

Immunity 20190401 4

The interleukin 17 (IL-17) family of cytokines contains 6 structurally related cytokines, IL-17A through IL-17F. IL-17A, the prototypical member of this family, just passed the 25<sup>th</sup> anniversary of its discovery. Although less is known about IL-17B-F, IL-17A (commonly known as IL-17) has received much attention for its pro-inflammatory role in autoimmune disease. Over the past decade, however, it has become clear that the functions of IL-17 are far more nuanced than simply turning on i ...[more]

PMID: 30995505

Similar Datasets

IL-17 family: cytokines, receptors and signaling.

Project description:The interleukin 17 (IL-17) family, a subset of cytokines consisting of IL-17A-F, plays crucial roles in host defense against microbial organisms and in the development of inflammatory diseases. Although IL-17A is the signature cytokine produced by T helper 17 (Th17) cells, IL-17A and other IL-17 family cytokines have multiple sources ranging from immune cells to non-immune cells. The IL-17 family signals via their correspondent receptors and activates downstream pathways that include NF?B, MAPKs and C/EBPs to induce the expression of anti-microbial peptides, cytokines and chemokines. The proximal adaptor Act1 is a common mediator during the signaling of all IL-17 cytokines so far and is thus involved in IL-17 mediated host defense and IL-17-driven autoimmune conditions. This review will give an overview and recent updates on the IL-17 family, the activation and regulation of IL-17 signaling as well as diseases associated with this cytokine family.

| S-EPMC3867811 | biostudies-literature

The IL-17 Family of Cytokines in Psoriasis: IL-17A and Beyond.

Project description:Psoriasis is a frequent chronic inflammatory skin disease, nowadays considered a major global health problem. Several new drugs, targeting the IL-23/IL-17A pathway, have been recently licensed or are in clinical development. These therapies represent a major improvement of the way in which psoriasis is managed, since they show an unprecedented efficacy on skin symptoms of psoriasis. This has been made possible, thanks to an increasingly more accurate pathogenic view of psoriasis. Today, the belief that Th17?cells mediate psoriasis is moving to the concept of psoriasis as an IL-17A-driven disease. New questions arise at the horizon, given that IL-17A is part of a newly described family of cytokines, which has five distinct homologous: IL-17B, IL-17C, IL-17D, IL-17E, also known as IL-25 and IL-17F. IL-17 family cytokines elicit similar effects in target cells, but simultaneously trigger different and sometimes opposite functions in a tissue-specific manner. This is complicated by the fact that IL-17 cytokines show a high capacity of synergisms with other inflammatory stimuli. In this review, we will summarize the current knowledge around the cytokines belonging to the IL-17 family in relation to skin inflammation in general and psoriasis in particular, and discuss possible clinical implications. A comprehensive understanding of the different roles played by the IL-17 cytokines is crucial to appreciate current and developing therapies and to allow an effective pathogenesis- and mechanisms-driven drug design.

| S-EPMC6088173 | biostudies-literature

Signalling of multiple interleukin (IL)-17 family cytokines via IL-17 receptor A drives psoriasis-related inflammatory pathways.

Project description:BackgroundThe interleukin (IL)-23/IL-17 immune axis is of central importance in psoriasis. However, the impact of IL-17 family cytokines other than IL-17A in psoriasis has not been fully established.ObjectivesTo elucidate the contribution of IL-17 family cytokines in psoriasis.MethodsTo address the expression and localization of IL-17 family cytokines, lesional and nonlesional skin samples from patients with psoriasis were analysed by several complementary methods, including quantitative polymerase chain reaction, immunoassays, in situ hybridization and immunohistochemistry. Mechanistic studies assessing the functional activity of IL-17 family cytokines were performed using ex vivo cultured human skin biopsies and primary human keratinocytes.ResultsWe demonstrated that IL-17A, IL-17F, IL-17A/F and IL-17C are expressed at increased levels in psoriasis lesional skin and induce overlapping gene expression responses in ex vivo cultured human skin that correlate with the transcriptomic signature of psoriasis skin. Furthermore, we showed that brodalumab, in contrast to ixekizumab, normalizes gene expression responses induced by the combination of IL-17A, IL-17F, IL-17A/F and IL-17C in human keratinocytes.ConclusionsSeveral IL-17 ligands signalling through IL-17RA are overexpressed in psoriasis skin and induce similar psoriasis-related inflammatory pathways demonstrating their relevance in relation to therapeutic intervention in psoriasis.

| S-EPMC8453543 | biostudies-literature

Much More Than IL-17A: Cytokines of the IL-17 Family Between Microbiota and Cancer.

Project description:The interleukin-(IL-)17 family of cytokines is composed of six members named IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. IL-17A is the prototype of this family, and it was the first to be discovered and targeted in the clinic. IL-17A is essential for modulating the interplay between commensal microbes and epithelial cells at our borders (i.e., skin and mucosae), and yet, for protecting us from microbial invaders, thus preserving mucosal and skin integrity. Interactions between the microbiota and cells producing IL-17A have also been implicated in the pathogenesis of immune mediated inflammatory diseases and cancer. While interactions between microbiota and IL-17B-to-F have only partially been investigated, they are by no means less relevant. The cellular source of IL-17B-to-F, their main targets, and their function in homeostasis and disease distinguish IL-17B-to-F from IL-17A. Here, we intentionally overlook IL-17A, and we focus instead on the role of the other cytokines of the IL-17 family in the interplay between microbiota and epithelial cells that may contribute to cancer pathogenesis and immune surveillance. We also underscore differences and similarities between IL-17A and IL-17B-to-F in the microbiota-immunity-cancer axis, and we highlight therapeutic strategies that directly or indirectly target IL-17 cytokines in diseases.

| S-EPMC7683804 | biostudies-literature

Multiple IL-17 family cytokines signaling through IL-17RA drive inflammatory pathways in psoriasis

Project description:The IL-23/IL-17 immune axis is of central importance in psoriasis. However, the contribution of IL-17 family cytokines other than IL-17A to drive skin inflammation in psoriasis has not been fully established. To further elucidate the role of individual IL-17 family cytokines in psoriasis, we investigated their expression and localization in psoriasis skin at the mRNA and protein level. Moreover, we investigated the gene expression signatures induced by individual IL-17 family cytokines in human skin ex vivo as well as modulation of responses induced by the combination of IL-17 family cytokines in human keratinocytes by brodalumab, a human monoclonal antibody targeting the IL-17RA, versus the IL-17A blocking antibody ixekizumab. We demonstrate that IL-17A, IL-17AF, IL-17F and IL-17C are expressed at increased levels in psoriasis lesional skin and induce inflammatory gene expression signatures in human skin ex vivo that correlate with those observed in psoriasis. Furthermore, we show that brodalumab, in contrast to ixekizumab, fully blocks gene expression responses induced by the combination of IL-17A, IL-17AF, IL-17F and IL-17C in human keratinocytes. These findings suggest that inhibition of several IL-17 family cytokines, e.g. by targeting of the IL-17RA receptor, could be a favored mechanism to obtain a profound suppression of the inflammatory processes in psoriasis and thereby achieve high levels of skin clearance and sustained efficacy in patients with psoriasis.

2021-04-07 | GSE158448 | GEO

IL-17 cytokines in immunity and inflammation.

Project description:Interleukin 17 (IL-17) and its closest relative, IL-17F, have recently drawn much attention in the field of immunology. IL-17 and IL-17F are expressed by a distinct type of T cells, T helper 17 cells and certain other lymphocytes. These cytokines play key regulatory roles in host defense and inflammatory diseases. In this review, we summarize the recent findings in IL-17 biology and the progress towards understanding the regulatory mechanisms of IL-17 expression and signaling mechanisms. This knowledge will benefit the development of novel immune modulators that enhance immunity to various infections and reduce inflammatory damage in infected patients.

| S-EPMC3820987 | biostudies-literature

Antibody blockade of IL-17 family cytokines in immunity to acute murine oral mucosal candidiasis.

Project description:Antibodies targeting IL-17A or its receptor, IL-17RA, are approved to treat psoriasis and are being evaluated for other autoimmune conditions. Conversely, IL-17 signaling is critical for immunity to opportunistic mucosal infections caused by the commensal fungus Candida albicans, as mice and humans lacking the IL-17R experience chronic mucosal candidiasis. IL-17A, IL-17F, and IL-17AF bind the IL-17RA-IL-17RC heterodimeric complex and deliver qualitatively similar signals through the adaptor Act1. Here, we used a mouse model of acute oropharyngeal candidiasis to assess the impact of blocking IL-17 family cytokines compared with specific IL-17 cytokine gene knockout mice. Anti-IL-17A antibodies, which neutralize IL-17A and IL-17AF, caused elevated oral fungal loads, whereas anti-IL-17AF and anti-IL-17F antibodies did not. Notably, there was a cooperative effect of blocking IL-17A, IL-17AF, and IL-17F together. Termination of anti-IL-17A treatment was associated with rapid C. albicans clearance. IL-17F-deficient mice were fully resistant to oropharyngeal candidiasis, consistent with antibody blockade. However, IL-17A-deficient mice had lower fungal burdens than anti-IL-17A-treated mice. Act1-deficient mice were much more susceptible to oropharyngeal candidiasis than anti-IL-17A antibody-treated mice, yet anti-IL-17A and anti-IL-17RA treatment caused equivalent susceptibilities. Based on microarray analyses of the oral mucosa during infection, only a limited number of genes were associated with oropharyngeal candidiasis susceptibility. In sum, we conclude that IL-17A is the main cytokine mediator of immunity in murine oropharyngeal candidiasis, but a cooperative relationship among IL-17A, IL-17AF, and IL-17F exists in vivo. Susceptibility displays the following hierarchy: IL-17RA- or Act1-deficiency > anti-IL-17A + anti-IL-17F antibodies > anti-IL-17A or anti-IL-17RA antibodies > IL-17A deficiency.

| S-EPMC4952011 | biostudies-literature

Divergent functions of IL-17-family cytokines in DSS colitis: Insights from a naturally-occurring human mutation in IL-17F.

Project description:The IL-17 family is structurally distinct from other cytokine subclasses. IL-17A and IL-17F, the most closely related of this family, form homodimers and an IL-17AF heterodimer. While IL-17A and IL-17F exhibit similar activities in many settings, in others their functions are divergent. To better understand the function of IL-17F in vivo, we created mice harboring a mutation in Il17f originally described in humans with unexplained chronic mucosal candidiasis (Ser-65-Leu). We evaluated Il17fS65L/S65L mice in DSS-colitis, as this is one of the few settings where IL-17A and IL-17F exhibit opposing activities. Specifically, IL-17A is protective of the gut epithelium, a finding that was revealed when trials of anti-IL-17A biologics in Crohn's disease failed and recapitulated in many mouse models of colitis. In contrast, mice lacking IL-17F are resistant to DSS-colitis, partly attributable to alterations in intestinal microbiota that mobilize Tregs. Here we report that Il17fS65L/S65L mice do not phenocopy Il17f-/- mice in DSS colitis, but rather exhibited a worsening disease phenotype much like Il17a-/- mice. Gut inflammation in Il17fS65L/S65L mice correlated with reduced Treg accumulation and lowered intestinal levels of Clostridium cluster XIV. Unexpectedly, the protective DSS-colitis phenotype in Il17f-/- mice could be reversed upon co-housing with Il17fS65L/S65L mice, also correlating with Clostridium cluster XIV levels in gut. Thus, the Il17fS65L/S65L phenotype resembles an IL-17A deficiency more closely than IL-17F deficiency in the setting of DSS colitis.

| S-EPMC8627693 | biostudies-literature

Antibody blockade of IL-17-family cytokines in immunity to acute murine oral mucosal candidiasis

Project description:IL17A KO mouse tongues after 2 days of C. albicans infection were profiled and compared to WT. In addition, tongues from animals infected for 2 days with C. albicans and then treated with anti-IL17A antibody, anti-IL17F antibody, anti-IL17A and anti-IL17F antibodies together, or isotypes controls were analyzed.

2015-12-21 | E-MTAB-4167 | biostudies-arrayexpress

Structure and function of interleukin-17 family cytokines.

Project description:The recently identified interleukin-17 (IL-17) cytokines family, which comprises six members in mammals (IL-17A-F), plays essential roles in the host immunity against infectious diseases and chronic inflammatory diseases. The three-dimensional structures containing IL-17A or IL-17F have become available and revealed the unique structural features of IL-17s as well as their receptors. Molecular modeling in this review shows that IL-17s may adopt a "cysteine knot" fold commonly seen in nerve growth factor (NGF) and other neurotrophins. Further modeling analysis unmasks a signature interaction feature of the IL-17F/IL-17RA complex, where a small loop of IL-17RA slots into the deep groove of the interface of IL-17F homodimer. This is quite different from the interaction between the best known four-helix cytokines and their cognate receptors. On the other hand, structure of IL-17A and its monoclonal antibody (CAT-2200) shows that, albeit that the antigenic epitope of IL-17A resides outside of the IL-17A homodimer interface, its physical proximity to the receptor binding groove may explain that antibody blockage would be achieved by interfering with the ligand-receptor interaction. This review is to summarize the advance in understanding the structure and function of IL-17 family cytokines, focusing mainly on IL-17A, IL-17F and IL-17E, in the hope of gaining better knowledge of immunotherapeutic strategies against various inflammatory diseases.

| S-EPMC4875287 | biostudies-literature

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