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Originally published In Press as doi:10.1074/jbc.M006393200 on August 14, 2000

J. Biol. Chem., Vol. 275, Issue 44, 34628-34633, November 3, 2000
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Antiproliferative Properties of Sphingosine 1-Phosphate in Human Hepatic Myofibroblasts
A CYCLOOXYGENASE-2 MEDIATED PATHWAY*

Julien DavailleDagger , Cyrille GalloisDagger , Aïda Habib§, Liying Li, Ariane Mallat, Jiangchuan Tao, Thierry Levade, and Sophie Lotersztajn||

From INSERM U99, Hopital Henri Mondor, Créteil 94010, France, § INSERM U348, Hopital Lariboisière, Paris 75010, France and  INSERM U466, CHU Rangueil, Toulouse 31403, France

Proliferation of hepatic myofibroblasts (hMF) is central for the development of fibrosis during liver injury, and factors that may limit their growth are potential antifibrotic agents. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with growth-regulating properties, either via Edg receptors or through intracellular actions. In this study, we examined the effects of S1P on the proliferation of human hMF. Human hMF expressed mRNAs for the S1P receptors Edg1, Edg3, and Edg5. These receptors were functional at nanomolar concentrations and coupled to pertussis toxin-sensitive and -insensitive G proteins, as demonstrated in guanosine 5'-3-O-(thio)triphosphate binding assays. S1P potently inhibited hMF growth (IC50 = 1 µM), in a pertussis toxin-insensitive manner. Analysis of the mechanisms involved in growth inhibition revealed that S1P rapidly increased prostaglandin E2 production and in turn cAMP, two growth inhibitory messengers for hMF; C2-ceramide and sphingosine, which inhibited hMF proliferation, did not affect cAMP levels. Production of cAMP by S1P was abolished by NS-398, a selective inhibitor of COX-2. Also, S1P potently induced COX-2 protein expression. Blocking COX-2 by NS-398 blunted the antiproliferative effect of S1P. We conclude that S1P inhibits proliferation of hMF, probably via an intracellular mechanism, through early COX-2-dependent release of prostaglandin E2 and cAMP, and delayed COX-2 induction. Our results shed light on a novel role for S1P as a growth inhibitory mediator and point out its potential involvement in the negative regulation of liver fibrogenesis.

* This work was supported in part by INSERM, the Université Paris-Val-de-Marne, and by grants from the Association pour la Recherche sur le Cancer (to S. L.) and the Ligue Départementale du Val d'Oise de la Recherche Contre le Cancer (to S. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Supported by fellowships from the Ministère de l'Enseignement et de la Recherche. Both authors contributed equally to this work.

|| To whom correspondence should be addressed: Unité INSERM 99, Hôpital Henri Mondor, 94010 Créteil, France. Tel.: 33-1-49 81 35 34; Fax: 33-1-48 98 09 08; E mail: loterszt@im3.inserm.fr.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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