C₂-ceramide inhibits the prostaglandin E₂-induced accumulation of cAMP in human gingival fibroblasts

抄録

Ceramide is generated by the hydrolysis of membrane sphingomyelin by sphingomyelinase and is implicated in multiple signaling pathways, including those regulating differentiation, inflammation and immune responses. Excess formation of prostaglandin E₂ (PGE₂) is thought to increase susceptibility to infection, rheumatoid arthritis and inflammation, including periodontal diseases. We investigated the inhibitory effect of C₂-ceramide, a short-chain ceramide analog, on the PGE₂-stimulated accumulation of cAMP in human gingival fibroblasts. In human gingival fibroblasts pre-treated with C₂-ceramide for 18 h, the PGE₂-stimulated accumulation of cAMP was reduced, but an inactive C₂-ceramide analog had no such effect. The accumulation of cAMP induced by EP2 and EP4 receptor agonists (ONO-AE1-259 and ONO-AE1-329, respectively) was inhibited in cells treated with C₂-ceramide. However, treatment with C₂-ceramide had no effect on the expression of mRNAs encoding the EP2 and EP4 receptors. Accumulation of cAMP could be induced by cAMP-elevating agents (forskolin, isobutylmethylxanthine and mastparan) but was not reduced by treatment with C₂-ceramide. These observations suggest that C₂-ceramide attenuates PGE₂ receptor function and consequently inhibits the accumulation of cAMP in human gingival fibroblasts.