Authors: Han, Weihong¹; Wang, Wei²; Mohammed, Kamal A.; Su, Yunchao

Source: FEBS Journal, Volume 276, Number 22, November 2009 , pp. 6603-6614(12)

Publisher: Wiley-Blackwell

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.

Keywords: β-catenin; collagen; defensins; fibroblasts; proliferation

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1742-4658.2009.07370.x

Affiliations: 1:  Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, USA 2:  Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA

Publication date: 2009-11-01

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• In this Subject: Anatomy & Physiology ,  Biology ,  Chemistry (General) ,  Biochemistry
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