期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 133, 期 6, 页码 1646-1654出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/jid.2013.28
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资金
- Canadian Institutes of Health Research [MOP-119410]
- Scleroderma Society of Ontario
Dermal connective tissue is a supportive structure required for skin's barrier function; dysregulated dermal homeostasis results in chronic wounds and fibrotic diseases. The multifunctional cytokine transforming growth factor (TGF) beta promotes connective tissue deposition, repair, and fibrosis. TGF-beta acts through well-defined canonical pathways; however, the non-canonical pathways through which TGF-beta selectively promotes connective tissue deposition are unclear. In dermal fibroblasts, we show that inhibition of the non-canonical TGF-beta-activated kinase 1 (TAK1) selectively reduced the ability of TGF-beta to induce expression of a cohort of wound healing genes, such as collagens, CCN2, TGF-beta 1, and IL-6. Fibroblast-specific TAK1-knockout mice showed impaired cutaneous tissue repair and decreased collagen deposition, alpha-smooth muscle actin and CCN2 expression, proliferating cell nuclear antigen staining, and c-Jun N-terminal kinase and p38, but not Smad3, phosphorylation. TAK1-deficient fibroblasts showed reduced cell proliferation, migration, cell attachment/spreading, and contraction of a floating collagen gel matrix. TAK1-deficient mice also showed progressively reduced skin thickness and collagen deposition. Thus, TAK1 is essential for connective tissue deposition in the dermis.
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