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J. Biol. Chem., Vol. 279, Issue 34, 35255-35262, August 20, 2004

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Sphingosine 1-Phosphate Cross-activates the Smad Signaling Cascade and Mimics Transforming Growth Factor--induced Cell Responses^*

Cuiyan Xin, Shuyu Ren, Burkhardt Kleuser, Soheyla Shabahang, Wolfgang Eberhardt, Heinfried Radeke, Monika Schäfer-Korting, Josef Pfeilschifter, and Andrea Huwiler¶

From the Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, and the Institut für Pharmakologie, Freie Universität Berlin, Koenigin-Luise-Strasse 2+4, D-14195 Berlin, Germany

Exposure of renal mesangial cells to sphingosine 1-phosphate (S1P) leads to a rapid and transient activation of the mitogen- and stress-activated protein kinases but also the protein kinase B. Here, we show that S1P also induces phosphorylation of Smad proteins, which are members of the transforming growth factor- (TGF-) signaling device. However, Smad phosphorylation occurred more slowly with a maximal effect after 20–30 min of S1P stimulation when compared with the rapid activation of the MAPKs. Interestingly, Smad phosphorylation is increased by pertussis toxin, which is in contrast to the complete inhibition of S1P-induced MAPK phosphorylation by pertussis toxin. TGF- is a potent anti-inflammatory cytokine, which in mesangial cells attenuates the expression of (i) inducible nitricoxide synthase (iNOS) caused by interleukin (IL)-1, (ii) secreted phospholipase A₂ (sPLA₂), and (iii) matrix metalloproteinase-9 (MMP-9). These gene products are also down-regulated by S1P in a concentration-dependent manner. Furthermore, the expression of connective tissue growth factor is enhanced by both TGF-₂ and S1P. These effects of S1P are not mediated by the MAPK cascade as neither pertussis toxin nor the MAPK cascade inhibitor U0126 are able to reverse this inhibition. Overexpression of the inhibitory Smad-7 or down-regulation of co-Smad-4 lead to a reversal of the blocking effect of S1P on IL-1-induced NO release. Moreover, down-regulating the TGF- receptor type II by the siRNA technique or antagonizing the S1P₃ receptor subtype with suramin abrogates S1P-stimulated Smad phosphorylation. In summary, our data show that S1P trans-activates the TGF- receptor and triggers activation of Smads followed by activation of connective tissue growth factor gene transcription and inhibition of IL-1-induced expression of iNOS, sPLA₂, and MMP-9.

Received for publication, November 4, 2003 , and in revised form, June 7, 2004.

^* This work was supported by grants from the Deutsche Forschungsgemeinschaft (HU 842/2-3 and PF361/2-1) and the Dr. H. Schleussner-Foundation for Immune Pharmacology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 49-69-6301-69-63; Fax: 49-69-6301-79-42; E-mail: Huwiler{at}em.uni-frankfurt.de.

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