Inactivation of the transcription factor STAT-4 prevents inflammation-driven fibrosis in animal models of systemic sclerosis

Arthritis Rheum. 2011 Mar;63(3):800-9. doi: 10.1002/art.30171.

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic
  • Bleomycin / toxicity
  • Cell Proliferation
  • Cytokines / immunology
  • Cytokines / metabolism
  • Dermis / immunology
  • Dermis / pathology
  • Disease Models, Animal
  • Female
  • Fibrosis / chemically induced
  • Fibrosis / immunology
  • Fibrosis / pathology
  • Genotype
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Phenotype
  • STAT4 Transcription Factor / genetics*
  • STAT4 Transcription Factor / immunology*
  • Scleroderma, Systemic* / genetics
  • Scleroderma, Systemic* / immunology
  • Scleroderma, Systemic* / pathology
  • Skin Diseases* / genetics
  • Skin Diseases* / immunology
  • Skin Diseases* / pathology
  • T-Lymphocytes / pathology

Substances

  • Antibiotics, Antineoplastic
  • Cytokines
  • STAT4 Transcription Factor
  • Stat4 protein, mouse
  • Bleomycin