RRC ID 68536
Author Kono Y, Nishiuma T, Nishimura Y, Kotani Y, Okada T, Nakamura S, Yokoyama M.
Title Sphingosine kinase 1 regulates differentiation of human and mouse lung fibroblasts mediated by TGF-beta1.
Journal Am J Respir Cell Mol Biol
Abstract Transforming growth factor beta (TGF-beta) contributes to the progression of pulmonary fibrosis through up-regulation of alpha-smooth muscle actin (alpha-SMA) as lung myofibroblast differentiation. Bioactive sphingosine 1-phosphate (S1P) has been shown to mimic TGF-beta signals; however, the function of S1P in lung fibrotic process has not been well documented. We found, in a mouse model of bleomycin lung fibrosis, that SPHK1 and alpha-SMA were colocalized within lung fibrotic foci and that these expressions were significantly increased in primary cultured fibroblasts. Using human lung fibroblasts WI-38, we explored the rationale of sphingosine kinase (SPHK) with TGF-beta1 stimulation. SPHK inhibitors and small interference RNA (siRNA) targeted SPHK1 decreased alpha-SMA and fibronectin expression up-regulated by TGF-beta1. In the meantime, SPHK1 inhibition did not affect smad2 phosphorylation in response to TGF-beta1. Then we examined whether S1P receptors transactivation may affect TGF-beta signals. siRNA against S1P(2) and S1P(3), but not S1P(1), reduced alpha-SMA expression as well as Y-27632, Rho kinase inhibitor. We also detected activation of Rho GTPase upon stimulation of TGF-beta1 on the cell membrane where S1P(2) or S1P(3) was overexpressed. These data suggested that SPHK1 activation by TGF-beta1 leads to Rho-associated myofibroblasts differentiation mediated by transactivated S1P receptors in the lung fibrogenic process.
Volume 37(4)
Pages 395-404
Published 2007-10-1
DOI 10.1165/rcmb.2007-0065OC
PII 2007-0065OC
PMID 17641298
MeSH Animals Bleomycin Cell Differentiation / drug effects* Cell Line Enzyme Activation / drug effects Female Fibroblasts / cytology* Fibroblasts / drug effects Fibroblasts / enzymology* Gene Silencing Humans Lung / cytology* Lung / drug effects Lung / enzymology* Mice Mice, Inbred C57BL Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors Phosphotransferases (Alcohol Group Acceptor) / genetics Phosphotransferases (Alcohol Group Acceptor) / metabolism* Protein Kinase Inhibitors / pharmacology Pulmonary Fibrosis / chemically induced Pulmonary Fibrosis / enzymology Pulmonary Fibrosis / pathology RNA, Small Interfering / metabolism Receptors, Lysosphingolipid / genetics Receptors, Lysosphingolipid / metabolism Signal Transduction / drug effects Smad2 Protein / metabolism Transcriptional Activation / drug effects Transforming Growth Factor beta1 / pharmacology* Up-Regulation / drug effects Up-Regulation / genetics rho GTP-Binding Proteins / metabolism
IF 5.373
Human and Animal Cells WI-38(RCB0702)