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

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 (TGF-) contributes to the progression of pulmonary fibrosis through up-regulation of –smooth muscle actin (–SMA) as lung myofibroblast differentiation. Bioactive sphingosine 1-phosphate (S1P) has been shown to mimic TGF- 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 –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-1 stimulation. SPHK inhibitors and small interference RNA (siRNA) targeted SPHK1 decreased –SMA and fibronectin expression up-regulated by TGF-1. In the meantime, SPHK1 inhibition did not affect smad2 phosphorylation in response to TGF-1. Then we examined whether S1P receptors transactivation may affect TGF- signals. siRNA against S1P₂ and S1P₃, but not S1P₁, reduced –SMA expression as well as Y-27632, Rho kinase inhibitor. We also detected activation of Rho GTPase upon stimulation of TGF-1 on the cell membrane where S1P₂ or S1P₃ was overexpressed. These data suggested that SPHK1 activation by TGF-1 leads to Rho-associated myofibroblasts differentiation mediated by transactivated S1P receptors in the lung fibrogenic process.

Key Words: S1P • SPHK1 • fibroblast • Rho • -SMA

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