期刊
PHARMACOLOGICAL RESEARCH
卷 57, 期 4, 页码 274-282出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2008.02.001
关键词
TGF-beta 1; ERK1/2; GSK-3 beta; beta-catenin; fibroblast; alpha-SMA
Transforming growth factor-alpha 1 (TGF-beta 1) is known to induce the transition of human lung fibroblasts to myofibroblasts, a primary event in the pathogenesis of idiopathic pulmonary fibrosis. The molecular pathways involved in myofibroblast transformation are only partially identified. We found that a 24-h treatment with TGF-beta 1 (10 ng/ml) induced alpha-smooth actin (SMA) expression and collagen production in human lung fibroblasts. These effects were abrogated by PD98059, a specific inhibitor of the mitogen-activated protein kinase (MAPK) pathway. TGF-beta 1 treatment activated the MAPK pathway, as shown by an increased phosphorylation of extracellular-regulated kinases (ERK)1/2 after 30 min of exposure. TGF-beta 1 also increased the expression of the Ser-9-phosphorylated inactive form of glycogen synthase kinase-3 beta (GSK-3 beta), an effect that was largely attenuated by PD98059. A nuclear translocation of beta-catenin in human lung fibroblasts was observed 2h after TGF-beta 1 addition both by confocal microscopy and nuclear protein analysis. At this time, TGF-beta 1 also increased the total levels of beta-catenin, an effect that was preventedby PD98059. Similarly to TGF-beta 1, the GSK-3 beta inhibitor lithium chloride (10 mM), increased the total levels of beta-catenin and promoted alpha-SMA expression and collagen production. This study demonstrates that TGF-beta 1 induces alpha-SMA expression and collagen production in human lung fibroblasts via ERK1/2 activation, GSK-3 beta inhibition and nuclear beta-catenin translocation. The evidence that the silencing of beta-catenin by siRNAs was able to prevent the induction of alpha-SMA expression in TGF-beta 1-treated fibroblasts further supports the hypothesis of a contribution of the GSK-3 beta/beta-catenin pathway in the pathogenesis of idiopathic pulmonary fibrosis. (C) 2008 Elsevier Ltd. All rights reserved.
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