title: Potential roles of interleukin-17A in the development of skin fibrosis in mice.
abstract: OBJECTIVE
  Although transforming growth factor β (TGFβ) and connective tissue growth factor (CTGF) have been considered to play central roles in the pathogenesis of systemic sclerosis (SSc), other cytokines may also be crucial for the development of SSc. The aim of this study was to examine the roles of T helper cytokines in the development of skin fibrosis.
  
  
  METHODS
  To compare the roles of Th1, Th2, and Th17 cytokines, we examined bleomycin-induced SSc in mice deficient for interferon-γ (IFNγ), interleukin-4 (IL-4), and IL-17A. The mechanism by which IL-17A contributes to bleomycin-induced fibrosis was investigated in vivo and in vitro. The outcome of mice lacking IL-17A was also investigated in TSK-1 mice.
  
  
  RESULTS
  The loss of IL-17A significantly attenuated bleomycin-induced skin fibrosis, whereas a deficiency of IFNγ or IL-4 did not. Leukocyte infiltration and the expression of TGFβ and CTGF messenger RNA in bleomycin-injected skin were significantly reduced in IL-17A-deficient mice compared with wild-type (WT) mice. Daily bleomycin injections induced the expression of IL-17A in the skin and potent IL-17A producers in splenic CD4+ T cells from WT mice. Furthermore, a skin fibroblast cell line expressed increased TGFβ, CTGF, and collagen after the addition of recombinant IL-17A. IL-17A deficiency also attenuated skin thickness in TSK-1 mice.
  
  
  CONCLUSIONS
  This study demonstrates that IL-17A contributes to skin fibrosis in 2 mouse models of SSc. These findings suggest that inhibition of IL-17A represents a therapeutic target for antagonizing fibrotic skin disorders such as SSc.
authors: Kanazawa University Graduate School of Medical Science, Japan.
authors: Yoshinobu
authors: Y
authors: Okamoto
authors: Minoru
authors: M
authors: Hasegawa
authors: Takashi
authors: T
authors: Matsushita
authors: Yasuhito
authors: Y
authors: Hamaguchi
authors: Doanh Le
authors: DL
authors: Huu
authors: Yoichiro
authors: Y
authors: Iwakura
authors: Manabu
authors: M
authors: Fujimoto
authors: Kazuhiko
authors: K
authors: Takehara
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000276:immunology / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D015847:Interleukin-4 / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D012867:Skin / Q000276:immunology* / Q000473:pathology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D000903:Antibiotics, Antineoplastic; C098680:Il17a protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17; D012333:RNA, Messenger; C475219:Tsk1 protein, mouse; D001761:Bleomycin; D018799:Intercellular Adhesion Molecule-1; D015847:Interleukin-4; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases