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Published ahead of print on July 19, 2007, doi:10.1165/rcmb.2007-0065OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 37, pp. 395-404, 2007
© 2007 American Thoracic Society
DOI: 10.1165/rcmb.2007-0065OC

Sphingosine Kinase 1 Regulates Differentiation of Human and Mouse Lung Fibroblasts Mediated by TGF-beta1

Yuko Kono1, Teruaki Nishiuma1, Yoshihiro Nishimura1, Yoshikazu Kotani1, Taro Okada2, Shun-ichi Nakamura2 and Mitsuhiro Yokoyama1

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

Correspondence and requests for reprints should be addressed to Yoshihiro Nishimura, M.D., Ph.D., Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. 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 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 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-beta1 on the cell membrane where S1P2 or S1P3 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.

Key Words: S1P • SPHK1 • fibroblast • Rho • {alpha}-SMA


CLINICAL RELEVANCE

This research shows a novel mechanism that sphingosine kinase 1 activation by TGF-beta1 leads to Rho-associated myofibroblast differentiation mediated by transactivated S1P receptors. Our data will help provide new insights into controlling clinical fibrotic diseases.

 



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