title: Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts.
abstract: Among IL-17 families, IL-17A and IL-17F share amino acid sequence similarity and bind to IL-17R type A. IL-17 signaling is implicated in the pathogenesis of various autoimmune diseases, but its role in the regulatory mechanism of extracellular matrix expression and its contribution to the phenotype of systemic sclerosis (SSc) both remain to be elucidated. This study revealed that IL-17A expression was significantly increased in the involved skin and sera of SSc patients, whereas the IL-17F levels did not increase. In contrast, the expression of IL-17R type A in SSc fibroblasts significantly decreased in comparison with that in normal fibroblasts, due to the intrinsic TGF-β1 activation in these cell types. Moreover, IL-17A, not IL-17F, reduced the protein expression of α1(I) collagen and connective tissue growth factor. miR-129-5p, one of the downregulated microRNAs in SSc fibroblasts, increased due to IL-17A and mediated the α1(I) collagen reduction. These results suggest that IL-17A signaling, not IL-17F, has an antifibrogenic effect via the upregulation of miR-129-5p and the downregulation of connective tissue growth factor and α1(I) collagen. IL-17A signaling is suppressed due to the downregulation of the receptor by the intrinsic activation of TGF-β1 in SSc fibroblasts, which may amplify the increased collagen accumulation and fibrosis characteristic of SSc. Increased IL-17A levels in the sera and involved skin of SSc may be due to negative feedback. Clarifying the novel regulatory mechanisms of fibrosis by the cytokine network consisting of TGF-β and IL-17A may lead to a new therapeutic approach for this disease.
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8555, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Nakashima
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Jinnin
authors.forename: Keitaro
authors.initials: K
authors.lastname: Yamane
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Honda
authors.forename: Ikko
authors.initials: I
authors.lastname: Kajihara
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Makino
authors.forename: Shinichi
authors.initials: S
authors.lastname: Masuguchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukushima
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Minoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ihn
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D003094:Collagen / Q000276:immunology / Q000378:metabolism*; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000276:immunology; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology; D008875:Middle Aged; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000276:immunology; D012595:Scleroderma, Systemic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology
chemical_list: C508717:IL17A protein, human; C440021:IL17F protein, human; D020381:Interleukin-17; D035683:MicroRNAs; D053722:Receptors, Interleukin-17; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D003094:Collagen