title: IL-21 induction of CD4+ T cell differentiation into Th17 cells contributes to bleomycin-induced fibrosis in mice.
abstract: Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and internal organs. Th17 cells and interleukin-17 (also called IL-17A) have been found to be increased in peripheral blood and skin in patients with SSc. IL-21 is a potent inducer of Th17 differentiation that is produced by activated T cells, and whose relationship with Th17 cells in SSc is unclear. Here, using a bleomycin (BLM)-induced mouse model of skin fibrosis, we detected the frequency of CD4+/IL-17+ (Th17) cells, CD4+/IL-21+ T cells and IL-21+ Th17 cells in peripheral blood, skin and lungs, as well as the serum content of IL-17A and IL-21. In addition, we assessed the differentiation of CD4+ T cells cultured from these mice into Th17 cells in response to treatment with IL-21. Compared with the control mice, Th17 cell counts and IL-17A levels were significantly increased and correlated with inflammatory and fibrotic indices in the skin and lungs of the BLM-induced fibrosis mice. Moreover, serum levels of CD4+/IL-21+ T cells, IL-21+ Th17 cells, and IL-21 were significantly increased in these mice, and correlated positively with serum levels of Th17 cells. In vitro experiments showed that IL-21 treated CD4+ T cells derived from BLM-induced mice differentiated into Th17 cells. Our results indicate that Th17 cells and IL-17A contributes to inflammatory and fibrotic processes in the skin and lungs in a BLM-induced mouse model of SSc. Moreover, the expansion of the Th17 cell population may be subsequent to IL-21 promotion of the differentiation of CD4+ T cells in these mice.
authors.affiliation: Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Lei
authors.forename: Xiao-Ning
authors.initials: XN
authors.lastname: Zhong
authors.forename: Zhi-Yi
authors.initials: ZY
authors.lastname: He
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhao
authors.forename: Xue-Jiao
authors.initials: XJ
authors.lastname: Sun
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006909:Hydroxyproline / Q000032:analysis; D020381:Interleukin-17 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000097:blood / Q000235:genetics / Q000494:pharmacology*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects; D000098546:Interleukin-21
chemical_list: C098680:Il17a protein, mouse; D020381:Interleukin-17; D007378:Interleukins; D011994:Recombinant Proteins; D001761:Bleomycin; D000098546:Interleukin-21; D006909:Hydroxyproline
keywords: CD4+ T cells; Th17 cells; interleukin-17; interleukin-21; systemic sclerosis