Journal
ARTHRITIS AND RHEUMATISM
Volume 63, Issue 3, Pages 800-809Publisher
WILEY-BLACKWELL
DOI: 10.1002/art.30171
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Funding
- Societe Francaise de Rhumatologie
- Groupe Francais de Recherche sur la Sclerodermie (Mutuelle AMPLI)
- Association des Sclerodermiques de France
- Pfizer
- Actelion
- Encysive
- FibroGen
- Ergonex
- NicOX
- Bristol-Myers Squibb
- Sanofi-Aventis
- United BioSource
- Medac
- Biovitrium
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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 alpha, interleukin-6 (IL-6), IL-2, and interferon-gamma 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.
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