α‐Defensins increase lung fibroblast proliferation and collagen synthesis via the β‐catenin signaling pathway

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Abstract
α‐defensins are released from granules of leukocytes and are implicated in inflammatory and fibrotic lung diseases. In the present study, the effects of α‐defensins on the proliferation and collagen synthesis of lung fibroblasts were examined. We found that α‐defensin‐1 and α‐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 α‐defensin‐1 and α‐defensin‐2 stimulate the proliferation of lung fibroblasts. α‐defensin‐1 and α‐defensin‐2 also increased collagen‐I mRNA (COL1A1) levels and protein contents of collagen‐I and active/dephosphorylated β‐catenin without changes in total β‐catenin protein content in lung fibroblasts (HFL‐1 and LL‐86). Inhibition of the β‐catenin signaling pathway using quercetin prevented increases in cell proliferation and the protein content of collagen‐I and active/dephosphorylated β‐catenin in lung fibroblasts, and in COL1A1 mRNA levels and collagen release into culture medium induced by α‐defensin‐1 and α‐defensin‐2. Knocking‐down β‐catenin using small interfering RNA technology also prevented α‐defensin‐induced increases in cell proliferation and the protein content of collagen‐I and active/dephosphorylated β‐catenin in lung fibroblasts, and in COL1A1 mRNA levels. Moreover, increases in the phosphorylation of glycogen synthase kinase 3β, accumulation/activation of β‐catenin, and collagen synthesis induced by α‐defensin‐1 and α‐defensin‐2 were prevented by p38 mitogen‐activated protein kinase inhibitor SB203580 and phosphoinositide 3‐kinase inhibitor LY294002. These results indicate that α‐defensin‐1 and α‐defensin‐2 stimulate proliferation and collagen synthesis of lung fibroblasts. The β‐catenin signaling pathway mediates α‐defensin‐induced increases in cell proliferation and collagen synthesis of lung fibroblasts. α‐defensin‐induced activation of β‐catenin in lung fibroblasts might be caused by phosphorylation/inactivation of glycogen synthase kinase 3β as a result of the activation of the p38 mitogen‐activated protein kinase and phosphoinositide 3‐kinase/Akt pathways.