title: A profibrotic role for thymic stromal lymphopoietin in systemic sclerosis.
abstract: OBJECTIVE
  [corrected] Systemic sclerosis (SSc) is an autoimmune disease characterised by progressive fibrosis. Although SSc shares pathogenetic features with other autoimmune diseases, the participation of profibrotic Th2 cytokines is unique to SSc, but the mechanisms of Th2 skewing are unknown. We have analysed the expression and function of thymic stromal lymphopoietin (TSLP), a central regulator of Th2-mediated allergic inflammation, in human SSc, primary lung fibrosis and in a mouse model of scleroderma.
  
  
  METHODS
  TSLP expression was analysed by immunohistochemistry in human SSc skin, primary lung fibrosis and mouse bleomycin-induced skin fibrosis, and by quantitative RT-PCR in mouse skin and cultured fibroblasts. The regulation of TSLP expression by specific toll-like receptors (TLR)-2, -3 and -4 agonists was analysed in human dermal fibroblast cultures. The role of TSLP in skin fibrosis and local cytokine expression was analysed in TSLP receptor (TSLPR)-deficient mice.
  
  
  RESULTS
  TSLP was overexpressed by epithelial cells, mast cells and fibroblasts in human SSc skin and lung fibrosis, and in the bleomycin model of scleroderma. In cultured human and mouse skin fibroblasts, TSLP expression was inducible by activation of TLR, particularly TLR3. In TSLPR-deficient mice, bleomycin-induced fibrosis was significantly reduced in parallel with significantly reduced local expression of IL-13.
  
  
  CONCLUSIONS
  These data provide the first evidence of TSLP overexpression in SSc and other non-allergic fibrotic conditions, and demonstrate a profibrotic role that is potentially meditated by specific changes in the local cytokine milieu. Thus, modulating TSLP may have antifibrotic therapeutic implications.
authors: Servicio de Reumatología, Instituto de Investigación Hospital 12 de Octubre (i+12), , Madrid, Spain.
authors: Alicia
authors: A
authors: Usategui
authors: Gabriel
authors: G
authors: Criado
authors: Elena
authors: E
authors: Izquierdo
authors: Manuel J
authors: MJ
authors: Del Rey
authors: Patricia E
authors: PE
authors: Carreira
authors: Pablo
authors: P
authors: Ortiz
authors: Warren J
authors: WJ
authors: Leonard
authors: José L
authors: JL
authors: Pablos
mesh_terms: D000818:Animals; D001761:Bleomycin; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D011658:Pulmonary Fibrosis / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000378:metabolism*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D051193:Toll-Like Receptors / Q000502:physiology; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D001761:Bleomycin; D000094632:Thymic Stromal Lymphopoietin
keywords: Autoimmunity; Cytokines; Fibroblasts; Systemic Sclerosis