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Pathobiology. 2006;73(5):224-37.

Increased bleomycin-induced skin fibrosis in mice lacking the Th1-specific transcription factor T-bet.

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  • 1Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611-2909, USA.

Abstract

Fibrosis, the pathological hallmark of scleroderma and related conditions, is due to sustained activation of tissue fibroblasts. Accumulating evidence implicates cytokine networks in initiating, and propagating or terminating fibroblast activation, and the specific cytokine phenotype dictates evolution of the fibrotic response toward either resolution or scarring. In particular, cytokines that promote fibroblast proliferation and myofibroblast differentiation and extracellular matrix (ECM) accumulation functionally define a type 2 (Th2) immune response, whereas interferon-gamma, which suppresses diverse fibroblast activities, defines a type 1 (Th1) immune response. It remains unclear what role the balance between Th1 and Th2 cytokines plays in the pathogenesis of fibrosis. Here we used bleomycin-induced skin fibrosis as a murine model for human scleroderma in order to study the fibrotic response in mice lacking T-bet, a transcription factor that is essential for initiating Th1 lineage development of CD4+ T lymphocytes. Spleen cells from T-bet null (T-bet(-/-)) mice exhibited a typical Th2 cytokine profile ex vivo, with elevated production of interleukin-4 (IL-4), IL-5 and IL-13, and diminished production of interferon-gamma. Bleomycin-induced early mast cells and eosinophil accumulation, and eosinophil degranulation, in the lesional tissue were greater in T-bet(-/-) mice than in wild-type control mice. At a later time point, T-bet(-/-) mice developed significantly more extensive dermal and especially hypodermal fibrosis. Elevated TGF-beta expression and intracellular Smad activation were prominent in lesional skin. Infiltrating eosinophils appeared to be an important cellular source of TGF-beta. These results demonstrate that in mice lacking T-bet bleomycin induced exaggerated skin fibrosis, suggesting that T-bet has an important physiologic role in regulation of tissue repair by promoting Th1 immune responses that prevent excessive ECM accumulation.

Copyright 2006 S. Karger AG, Basel.

PMID:
17314493
[PubMed - indexed for MEDLINE]
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