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Journal of Lipid Research, Vol. 48, 1985-1996, September 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Sphingosylphosphorylcholine acts in an anti-inflammatory manner in renal mesangial cells by reducing interleukin-1ß-induced prostaglandin E₂ formation

Cuiyan Xin^1,*, Shuyu Ren^1,*, Wolfgang Eberhardt, Josef Pfeilschifter and Andrea Huwiler^2,*,

^* Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland
Pharmazentrum Frankfurt/Zentrum für Arzneimittel Forschung Entwicklung und Sicherheit, Klinikum der Johann Wolfgang Goethe-Universität, D-60590 Frankfurt am Main, Germany

Published, JLR Papers in Press, June 25, 2007.

¹ C. Xin and S. Ren contributed equally to this work.

² To whom correspondence should be addressed. e-mail: huwiler{at}pki.unibe.ch

Sphingosylphosphorylcholine (SPC) is a bioactive lipid that binds to G protein-coupled-receptors and activates various signaling cascades. Here, we show that in renal mesangial cells, SPC not only activates various protein kinase cascades but also activates Smad proteins, which are classical members of the transforming growth factor-ß (TGFß) signaling pathway. Consequently, SPC is able to mimic TGFß-mediated cell responses, such as an anti-inflammatory and a profibrotic response. Interleukin-1ß-stimulated prostaglandin E₂ formation is dose-dependently suppressed by SPC, which is paralleled by reduced secretory phospholipase A₂ (sPLA₂) protein expression and activity. This effect is due to a reduction of sPLA₂ mRNA expression caused by inhibited sPLA₂ promoter activity. Furthermore, SPC upregulates the profibrotic connective tissue growth factor (CTGF) protein and mRNA expression. Blocking TGFß signaling by a TGFß receptor kinase inhibitor causes an inhibition of SPC-stimulated Smad activation and reverses both the negative effect of SPC on sPLA₂ expression and the positive effect on CTGF expression. In summary, our data show that SPC, by mimicking TGFß, leads to a suppression of proinflammatory mediator production and stimulates a profibrotic cell response that is often the end point of an anti-inflammatory reaction. Thus, targeting SPC receptors may represent a novel therapeutic strategy to cope with inflammatory diseases.

Supplementary key words transforming growth factor-ß₂ • Smad • secretory phospholipase A₂ • connective tissue growth factor

Abbreviations: COX-2, cyclooxygenase-2; CTGF, connective tissue growth factor; GPR4, G protein-coupled receptor 4; IL-1ß, interleukin-1ß; LPC, lysophosphatidylcholine; MAPK, mitogen-activated protein kinase; PGE₂, prostaglandin E₂; PKB, protein kinase B; PLA₂, phospholipase A₂; S1P, sphingosine 1-phosphate; SBE, Smad binding element; siRNA, small interfering RNA; SM, sphingomyelin; SPC, sphingosylphosphorylcholine; sPLA₂, secretory phospholipase A₂; TGFß, transforming growth factor-ß; TIE, transforming growth factor-ß inhibitory element; TKI, transforming growth factor-ß receptor type I kinase inhibitor

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