Pro-Inflammatory Role of SIP3 in Macrophages

Sphingosine kinase 1 and its product, sphingosine 1-phosphate (SIP), as well as their receptors, have been implicated in inflammatory responses. The functions of receptors S1P(1) and S1P(2) on cell motility have been investigated. However, the function of S1P(3) has been poorly investigated. In this study, the roles of S1P(3) on inflammatory response were investigated in primary peritoneal macrophages. S1P(3) receptor was induced along with sphingosine kinase 1 by stimulation of lipopolysaccharide (LPS). LPS treatment induced inflammatory genes, such iNOS, COX-2, IL-1 beta, IL-6 and TNF-alpha. TY52156, an antagonist of S1 P 3 suppressed the induction of inflammatory genes in a concentration dependent manner. Suppression of iNOS and COX-2 induction was further confirmed by western blotting and NO measurement. Suppression of IL-1 beta induction was also confirmed by western blotting and ELISA. Caspase 1, which is responsible for IL-1 beta production, was similarly induced by LPS and suppressed by TY52156. Therefore, we have shown S1P(3) induction in the inflammatory conditions and its pro-inflammatory roles. Targeting S1P(3) might be a strategy for regulating inflammatory diseases.