Submitted on February 12, 2007
Revised on June 19, 2007
Accepted on June 24, 2007
Sphingosylphosphorylcholine acts in an anti-inflammatory manner in renal mesangial cells by reducing interleukin-1
-induced prostaglandin E2 formation
Cuiyan Xin, Shuyu Ren, Wolfgang Eberhardt, Josef Pfeilschifter, and Andrea Huwiler
Pharmacology, University of Bern, Bern CH-3010
Corresponding Author: Huwiler{at}pki.unibe.ch
Sphingosylphosphorylcholine (SPC) is a bioactive lipid that binds to G-protein-coupled-receptors and activates various signalling 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 (TGF)beta signalling pathway. Consequently, SPC is able to mimic TGFbeta-mediated cell responses such as an anti-inflammatory and a pro-fibrotic response. Interleukin-1beta-stimulated prostaglandin E2 (PGE2) 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 pro-fibrotic connective tissue growth factor (CTGF) protein and mRNA expression. Blocking TGFbeta signalling by a TGFbeta-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 TGFbeta, leads to a suppression of proinflammatory mediator production and stimulates a pro-fibrotic cell response which is often the end point of an antiinflammatory reaction. Thus, targeting SPC-receptors may represent a novel therapeutic strategy to cope with inflammatory diseases.
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