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Contrary effects of sphingosine-1-phosphate on expression of -smooth muscle actin in transforming growth factor 1-stimulated lung fibroblasts

Kawashima, T;Yamazaki, R;Matsuzawa, Y;Yamaura, E;Takabatake, M;Otake, S;Ikawa, Y;Nakamura, H;Fujino, H;Murayama, T;

Transforming growth factor-1 (TGF1) plays a pivotal role in fibrosis in various organs including the lung. Following pulmonary injury, TGF1 stimulates conversion of fibroblasts to myofibroblasts that are mainly characterized by up-regulation of -smooth muscle actin (SMA) expression, and the resulting excess production of extracellular matrix proteins causes fibrosis with loss of alveolar function. The present study was undertaken to define the role of the sphingosine-1-phosphate (S1P) pathway in TGF1-induced expression of SMA in human fetal lung fibroblasts, HFL1 cells. Analysis of mRNA revealed the existence of S1P(1), S1P(2), and S1P(3) receptor mRNAs. Treatment with TGF1 increased sphingosine kinase (SphK) activity and S1P(3) receptor mRNA at 24h after stimulation, and pharmacological data showed the involvement of sphingomyelinase, SphK, and S1P(3) receptor in the TGF1-induced up-regulation of SMA with and without serum. Treatment with pertussis toxin and S1P(1) receptor antagonist W146 enhanced SMA expression by TGF1/serum, and S1P decreased and increased SMA levels with and without serum, respectively. TGF1 increased cyclooxygenase-2 expression in a manner dependent on serum and the sphingomyelinase/SphK pathway, and the response was decreased by pertussis toxin. Prostaglandin E(2), formed by TGF1/serum stimulation, decreased the TGF1-induced expression of SMA via EP prostanoid receptor. These data suggest that S1P formed by TGF1 stimulation has diverse effects on the expression of SMA, inhibition via the S1P(1) receptor-mediated and serum-dependent expression of cyclooxygenase-2 and the resulting formation of prostaglandin E(2), and stimulation via the S1P(3) receptor in a serum-independent manner.