Structure and signaling in the IL-17 receptor family

University of Pittsburgh, Department of Medicine, Division of Rheumatology and Clinical Immunology, Pittsburgh, Pennsylvania 15261, USA.
Nature Reviews Immunology (Impact Factor: 34.99). 09/2009; 9(8):556-67. DOI: 10.1038/nri2586
Source: PubMed


Interleukin-17A (IL-17A), the hallmark cytokine of the newly defined T helper 17 (T(H)17) cell subset, has important roles in protecting the host against extracellular pathogens, but also promotes inflammatory pathology in autoimmune disease. IL-17A and its receptor (IL-17RA) are the founding members of a newly described family of cytokines and receptors that have unique structural features which distinguish them from other cytokine families. Research defining the signal transduction pathways induced by IL-17R family cytokines has lagged behind that of other cytokine families, but studies in the past 2 years have begun to delineate unusual functional motifs and new proximal signalling mediators used by the IL-17R family to mediate downstream events.

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    • "Hindawi Publishing Corporation Mediators of Inflammation Volume 2015, Article ID 470458, 11 pages Mediators of Inflammation all tested cells [17] [18] [19] "
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    ABSTRACT: Adult stem cells have a great potential applicability in regenerative medicine and cell-based therapies. However, there are still many unresolved issues concerning their biology, and the influence of the local microenvironment on properties of stem cells has been increasingly recognized. Interleukin (IL-) 17, as a cytokine implicated in many physiological and pathological processes, should be taken into consideration as a part of a regulatory network governing tissue-associated stem cells’ fate. This review is focusing on the published data on the effects of IL-17 on the properties and function of hematopoietic and mesenchymal stem cells and trying to discuss that IL-17 achieves many of its roles by acting on adult stem cells.
    Full-text · Article · May 2015 · Mediators of Inflammation
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    • "Th17, which have been detected in dermal infiltrates of psoriatic lesions as well as in synovial fluid (Lowes et al., 2008). This cytokine specifically acts on keratinocytes increasing the expression of other chemokines, which recruit most of the cells participating to the plaque formation, i.e. mDCs, Th17 cells, and neutrophils (Gaffen, 2009; Lin et al., 2011). The key regulator cytokine for Th17 and IL-17 production is IL-23, mainly synthesized by DCs (Jariwala, 2007). "
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    ABSTRACT: Among the several cytokines involved in the psoriasis pathogenesis, tumor necrosis factor (TNF)-alpha and interleukin (IL)-17 play a central role. Many biomolecular steps remain unknown due to difficulty to obtain psoriatic models. To investigate the effect of TNF-alpha and IL-17 on the ultrastructure, immunophenotype, and number of epidermal Langerhans cells (LCs), human skin explants (n = 7) were cultured air–liquid interface in a Transwell system. Four different conditions were used: medium alone (control), medium added with 100 ng/ml TNF-alpha or 50 ng/ml IL-17 or a combination of both cytokines. Samples were harvested 24 and 48 h after cytokine addition and were frozen. Samples harvested at 24 h were also processed for transmission electron microscopy (TEM). By immunofluorescence analysis with anti-human Langerin antibody (three experiments/sample) we calculated the percentage of LCs/mm2 of living epidermis after 24 and 48 h of incubation (considering control as 100%). At 24 h LC number was significantly higher in samples treated with both cytokines (216.71 + 15.10%; p < 0.001) and in TNF-alpha (125.74 + 26.24%; p < 0.05). No differences were observed in IL-17-treated samples (100.14 + 38.42%). After 48 h, the number of epidermal Langerin-positive cells in IL-17- and TNF-alpha treated samples slightly decreased (94.99 + 36.79% and 101.37 + 23% vs. their controls, respectively). With the combination of both cytokines epidermal LCs strongly decreased (120 + 13.36%).
    Full-text · Article · Dec 2014 · European Journal of Cell Biology
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    • "IL-17F shares 44% amino acids with IL-17A, whereas the other members share a more limited 15–27% identity. IL-17A and IL-17F can be secreted as disulfide-linked homo- or hetero-dimers and bind the same IL-17RA IL-17RC heterodimeric receptor [24], [25]. In general, IL-17F shares functions with IL-17A, but at variance with IL-17A, IL-17F did not inhibit collagen production induced in fibroblasts by TGF-β [23], although both IL-17A and IL-17F modulated the function of fibrocytes upon CD40 engagement [26]. "
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    ABSTRACT: Background High interleukin (IL)-17A levels are characteristically found in the skin of systemic sclerosis (SSc) individuals. Our aim was to investigate whether the dermal expression of IL-17A and related IL-17 family members (i.e. IL-17C, IL-17E and IL-17F) could distinguish fibrotic from healthy skin and could show similarities in SSc and morphea, two disorders with presumed distinct pathogenesis, but characterized by skin fibrosis. Methods Biopsies were obtained from the involved skin of 14 SSc, 5 morphea and 8 healthy donors (HD) undergoing plastic surgery. Immunohistochemistry/immunofluorescence techniques were coupled to a semi-automated imaging quantification approach to determine the presence of the IL-17 family members in the skin. The in vitro effects induced by the IL-17 family members on fibroblasts from normal and SSc individuals were assessed by ELISA and RIA. Results Positive cells for each of the IL-17 isoforms investigated were present in the dermis of all the individuals tested, though with variable frequencies. SSc individuals had increased frequency of IL-17A+ (p = 0.0237) and decreased frequency of IL-17F+ (p = 0.0127) and IL-17C+ cells (p = 0.0008) when compared to HD. Similarly, morphea individuals had less frequent IL-17C+ cells (p = 0.0186) in their skin but showed similar number of IL-17A+ and IL-17F+ cells when compared to HD. Finally, IL-17E+ cells were more numerous in morphea (p = 0.0109) and tended to be more frequent in SSc than in HD. Fibroblast production of IL-6, MMP-1 and MCP-1 was enhanced in a dose-dependent manner in the presence of IL-17E and IL-17F, but not in the presence of IL-17C. None of the cytokine tested had significant effect on type I collagen production. Of interest, in SSc the frequency of both IL-17A and IL-17F positive cells increased with disease duration. Conclusions The frequency of IL-17A and IL-17F distinguish SSc to morphea individuals while dermal expression of IL-17C (low) and IL-17E (high) identifies a fibrosis-specific motif. The specific IL-17C/IL-17E cytokine combination may thus play a role in the development of fibrosis.
    Full-text · Article · Aug 2014 · PLoS ONE
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