Apolipoprotein M induces inhibition of inflammatory responses via the S1PR1 and DHCR24 pathways.

ABSTRACT

Apolipoprotein M (ApoM) is a type of apolipoprotein. It is well known that high­density lipoprotein (HDL) decreases inflammatory responses via the apoM­sphingosine­1­phosphate (S1P) pathway. The present study further investigated the importance of ApoM in the inhibitory effects of HDL on inflammation. Mice with an apoM gene deficiency (apoM­/­) were employed to investigate the effects of ApoM on the expression of interleukin­1ß (IL­1ß), monocyte chemotactic protein­1 (MCP­1), S1P receptor­1 (S1PR1) and 3ß­hydroxysterol Δ­24­reductase (DHCR24), as compared with in wild­type mice (apoM+/+). Furthermore, cell culture experiments were performed using a permanent human hybrid endothelial cell line (EA.hy926). Cells were cultured in the presence of recombinant human apoM (rec­apoM) or were induced to overexpress apoM (apoMTg); subsequently, cells were treated with tumor necrosis factor­α (TNF­α), in order to investigate the effects of ApoM on IL­1ß and MCP­1. The results demonstrated that the mRNA expression levels of IL­1ß and MCP­1 were significantly higher in the liver following administration of lipopolysaccharide in apoM­/­ mice compared with in apoM+/+ mice. In cell culture experiments, when cells were pre­cultured with rec­apoM or were engineered to overexpress apoM (apoMTg), they exhibited decreased expression levels of IL­1ß and MCP­1 following TNF­α treatment compared with in normal apoM­expressing cells (apoMTgN). Furthermore, the mRNA expression levels of IL­1ß and MCP­1 were significantly elevated following addition of the S1PR1 inhibitor W146, but not by the scavenger receptor class B type I inhibitor, block lipid transport­1 (BLT­1), in apoMTg cells prior to TNF­α treatment. Conversely, there were no differences in these inflammatory biomarkers under the same conditions in apoMTgN cells. The mRNA expression levels of DHCR24 were significantly reduced by the addition of BLT­1 prior to TNF­α treatment in apoMTg cells; however, there was no difference in the expression of this inflammatory biomarker in apoMTgN cells. In conclusion, ApoM displayed inhibitory effects against the inflammatory response in vivo and in vitro; these effects may be induced via the S1PR1 and DHCR24 pathways.