期刊
FEBS JOURNAL
卷 276, 期 22, 页码 6603-6614出版社
WILEY
DOI: 10.1111/j.1742-4658.2009.07370.x
关键词
beta-catenin; collagen; defensins; fibroblasts; proliferation
资金
- NIH [R01HL088261]
- Flight Attendant Medical Research Institute [032040, 072104]
- American Heart Association Greater Southeast Affiliate [0555322B, 0855338E]
alpha-defensins are released from granules of leukocytes and are implicated in inflammatory and fibrotic lung diseases. In the present study, the effects of alpha-defensins on the proliferation and collagen synthesis of lung fibroblasts were examined. We found that alpha-defensin-1 and alpha-defensin-2 induced dose-dependent increases in the incorporation of 5-bromo-2'-deoxy-uridine into newly synthesized DNA in two lines of human lung fibroblasts (HFL-1 and LL-86), suggesting that alpha-defensin-1 and alpha-defensin-2 stimulate the proliferation of lung fibroblasts. alpha-defensin-1 and alpha-defensin-2 also increased collagen-I mRNA (COL1A1) levels and protein contents of collagen-I and active/dephosphorylated beta-catenin without changes in total beta-catenin protein content in lung fibroblasts (HFL-1 and LL-86). Inhibition of the beta-catenin signaling pathway using quercetin prevented increases in cell proliferation and the protein content of collagen-I and active/dephosphorylated beta-catenin in lung fibroblasts, and in COL1A1 mRNA levels and collagen release into culture medium induced by alpha-defensin-1 and alpha-defensin-2. Knocking-down beta-catenin using small interfering RNA technology also prevented alpha-defensin-induced increases in cell proliferation and the protein content of collagen-I and active/dephosphorylated beta-catenin in lung fibroblasts, and in COL1A1 mRNA levels. Moreover, increases in the phosphorylation of glycogen synthase kinase 3 beta, accumulation/activation of beta-catenin, and collagen synthesis induced by alpha-defensin-1 and alpha-defensin-2 were prevented by p38 mitogen-activated protein kinase inhibitor SB203580 and phosphoinositide 3-kinase inhibitor LY294002. These results indicate that alpha-defensin-1 and alpha-defensin-2 stimulate proliferation and collagen synthesis of lung fibroblasts. The beta-catenin signaling pathway mediates alpha-defensin-induced increases in cell proliferation and collagen synthesis of lung fibroblasts. alpha-defensin-induced activation of beta-catenin in lung fibroblasts might be caused by phosphorylation/inactivation of glycogen synthase kinase 3 beta as a result of the activation of the p38 mitogen-activated protein kinase and phosphoinositide 3-kinase/Akt pathways.
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