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Published ahead of print on July 19, 2007, doi:10.1165/rcmb.2007-0065OC

Am. J. Respir. Cell Mol. Biol., Volume 37, Number 4, October 2007, 395-404

A more recent version of this article appeared on October 1, 2007
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Submitted on February 28, 2007
Revised on July 18, 2007

Sphingosine Kinase 1 Regulates Differentiation of Human and Mouse Lung Fibroblasts Mediated by TGF{beta}1

Yuko Kono1, Teruaki Nishiuma1, Yoshihiro Nishimura1*, Yoshikazu Kotani1, Taro Okada1, Shun-ichi Nakamura2, and Mitsuhiro Yokoyama1

1 Department of Internal Medicine, Kobe University Graduate School of Medicine, Division of Cardiovascular and Respiratory Medicine, Kobe, Japan, 2 Department of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Division of Biochemistry, Kobe, Japan

* To whom correspondence should be addressed. E-mail: nishiy{at}med.kobe-u.ac.jp.

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 myofibroblasts 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 mouse bleomycin lung fibrosis model, SPHK1 and {alpha}SMA were colocalized within lung fibrotic foci and 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{beta}1 stimulation. SPHK inhibitors and small interference RNA (siRNA) targeted SPHK1 decreased {alpha}SMA and fibronectin expression up-regulated by TGF{beta}1. In the meantime, SPHK1 inhibition did not affect smad2 phosphorylation in response to TGF{beta}1. Then we examined whether S1P receptors transactivation may affect TGF{beta} signals. siRNA against S1P2 and S1P3, but not S1P1, reduced {alpha}SMA expression as well as Y-27632, Rho kinase inhibitor. We also detected activation of Rho GTPase upon stimulation of TGF{beta}1 on the cell membrane where S1P2 or S1P3 was overexpressed. These data suggested that SPHK1 activation by TGF{beta}1 leads to Rho-associated myofibroblasts differentiation mediated by transactivated S1P receptors in the lung fibrogenic process.




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