RGD Reference Report - Inactivation of the transcription factor STAT-4 prevents inflammation-driven fibrosis in animal models of systemic sclerosis. - Rat Genome Database

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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.
RGD ID: 8661691
Pubmed: PMID:21360510   (View Abstract at PubMed)
DOI: DOI:10.1002/art.30171   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
STAT4HumanDermal Fibrosis  ISOStat4 (Mus musculus) RGD 
Stat4RatDermal Fibrosis  ISOStat4 (Mus musculus) RGD 
Stat4MouseDermal Fibrosis  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Stat4  (signal transducer and activator of transcription 4)

Genes (Mus musculus)
Stat4  (signal transducer and activator of transcription 4)

Genes (Homo sapiens)
STAT4  (signal transducer and activator of transcription 4)


Additional Information