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

Authors: Avouac, J  Furnrohr, BG  Tomcik, M  Palumbo, K  Zerr, P  Horn, A  Dees, C  Akhmetshina, A  Beyer, C  Distler, O  Schett, G  Allanore, Y  Distler, JH 
Citation: Avouac J, etal., Arthritis Rheum. 2011 Mar;63(3):800-9. doi: 10.1002/art.30171.
Pubmed: (View Article at PubMed) PMID:21360510
DOI: Full-text: DOI:10.1002/art.30171

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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CRRD Object Information
CRRD ID: 8661691
Created: 2014-06-12
Species: All species
Last Modified: 2014-06-12
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.