Sphingosylphosphorylcholine acts in an anti-inflammatory manner in renal mesangial cells by reducing interleukin-1beta-induced prostaglandin E2 formation.
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-beta (TGFbeta) signaling pathway. Consequently, SPC is able to mimic TGFbeta-mediated cell responses, such as an anti-inflammatory and a profibrotic response. Interleukin-1beta-stimulated prostaglandin E(2) formation is dose-dependently suppressed by SPC, which is paralleled by reduced secretory phospholipase A(2) (sPLA(2)) protein expression and activity. This effect is due to a reduction of sPLA(2) mRNA expression caused by inhibited sPLA(2) promoter activity. Furthermore, SPC upregulates the profibrotic connective tissue growth factor (CTGF) protein and mRNA expression. Blocking TGFbeta signaling by a TGFbeta receptor kinase inhibitor causes an inhibition of SPC-stimulated Smad activation and reverses both the negative effect of SPC on sPLA(2) 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 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.
Xin
Cuiyan
C
Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland.
Ren
Shuyu
S
Eberhardt
Wolfgang
W
Pfeilschifter
Josef
J
Huwiler
Andrea
A
D000818:Animals; D002478:Cells, Cultured; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors*; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000502:physiology
D053583:Interleukin-1beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015232:Dinoprostone; D013110:Sphingosine