Abstract
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.
Highlights
Sphingosylphosphorylcholine (SPC) is a bioactive lipid that binds to G protein-coupled-receptors and activates various signaling cascades
We show that SPC is able to act on mesangial cells to rapidly activate various signaling cascades, including the mitogen- and stress-activated protein kinases, protein kinase B (PKB), and the Smad proteins, which are members of the transforming growth factor-b (TGFb) signaling device
Because a delayed and sustained phase of mitogen-activated protein kinase (MAPK) activation has been suggested as a prerequisite for cell proliferation [22, 25], this increase at 60 min may be an indication of the proliferative nature of SPC reported previously by others [26]
Summary
Sphingosylphosphorylcholine (SPC) is a bioactive lipid that binds to G protein-coupled-receptors and activates various signaling cascades. Interleukin-1b-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. GPR12 was reported as unresponsive to SPC [8], and SPC binding to GPR4 could not be confirmed by Bektas et al [9] Considering these latter negative reports, it is clear that the high-affinity SPC receptors responsible for SPCtriggered signal transduction and SPC-induced cell responses still need to be identified. Similar to S1P and LPC, SPC acts by binding to and activating cell surface
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