title: Inactivation of the transcription factor STAT-4 prevents inflammation-driven fibrosis in animal models of systemic sclerosis.
abstract: OBJECTIVE
  The transcription factor STAT-4 has recently been identified as a genetic susceptibility factor in systemic sclerosis (SSc) and other autoimmune diseases. The aim of this study was to investigate the contribution of STAT-4 in the development of a fibrotic phenotype in 2 different mouse models of experimental dermal fibrosis.
  
  
  METHODS
  STAT-4-deficient (stat4(-/-) ) mice and their wild-type littermates (stat4(+/+) ) were injected with bleomycin or NaCl. Infiltrating leukocytes, T cells, B cells, and monocytes were quantified in the lesional skin of stat4(-/-) and stat4(+/+) mice. Inflammatory and profibrotic cytokines were measured in sera and lesional skin samples from stat4(-/-) and stat4(+/+) mice. The outcome of mice lacking STAT-4 was also investigated in the tight skin 1 (TSK-1) mouse model.
  
  
  RESULTS
  Stat4(-/-) mice were protected against bleomycin-induced dermal fibrosis, with a reduction in dermal thickening (mean ± SEM 65 ± 3% decrease; P = 0.03), hydroxyproline content (68 ± 5% decrease; P = 0.02), and myofibroblast counts (71 ± 6% decrease; P = 0.005). Moreover, the number of infiltrating leukocytes, especially T cells, was significantly decreased in the lesional skin of stat4(-/-) mice (mean ± SEM 63 ± 5% reduction in T cell count; P = 0.02). Stat4(-/-) mice also displayed decreased levels of inflammatory cytokines such as tumor necrosis factor α, interleukin-6 (IL-6), IL-2, and interferon-γ in lesional skin. Consistent with a primary role of STAT-4 in inflammation, STAT-4 deficiency did not ameliorate fibrosis in TSK-1 mice.
  
  
  CONCLUSIONS
  The results of this study demonstrate that the transcription factor STAT-4 exerts potent profibrotic effects by controlling T cell activation and proliferation and cytokine release. These findings confirm the results of genetics studies on the role of STAT-4 in the development of SSc.
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany. javouac@me.com
authors.forename: Jérôme
authors.initials: J
authors.lastname: Avouac
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Fürnrohr
authors.forename: Michal
authors.initials: M
authors.lastname: Tomcik
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.forename: Angelika
authors.initials: A
authors.lastname: Horn
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Alfiya
authors.initials: A
authors.lastname: Akhmetshina
authors.forename: Christian
authors.initials: C
authors.lastname: Beyer
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic; D001761:Bleomycin / Q000633:toxicity; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D020405:Dermis / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D005838:Genotype; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010641:Phenotype; D050797:STAT4 Transcription Factor / Q000235:genetics* / Q000276:immunology*; D012595:Scleroderma, Systemic / Q000235:genetics / Q000276:immunology / Q000473:pathology; D012871:Skin Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000473:pathology
chemical_list: D000903:Antibiotics, Antineoplastic; D016207:Cytokines; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D001761:Bleomycin