Calcineurin is involved in inflammatory responses in human gingival fibroblasts

点击翻译按钮获取中文摘要

Calcineurin is a calcium-activated serine/threonine phosphatase critical to a number of developmental processes in the immune systems. The role of Calcineurin in the immune response is underscored by the calcineurin inhibitors, such as cyclosporin A and FK506. We have previously demonstrated that pro-inflammatory cytokines, IL-16 and TNF-a induced PGE_2 release in human gingival fibroblasts. In this research project, we investigated whether Calcineurin inhibitors affect PGE_2 synthesis in human gingival fibroblasts. We analyzed the effects of cyclosporin A and FK506 on the PGE_2 release and the expression of cyclooxygenase-2 mRNA.Cyclosporin A induced cyclooxygenase-2 expression as well as prostaglandin E_2 release. This induction was more prominent when human gingival fibroblasts were treated with IL-16. Cyclosprin A induced PGE2 release in dose-and time-dependent manner, and reached a maximum at 10 μM for 24h. Cyclosporin A and FK506 partially increased IL-18-mediated PGE_2 release. Moreover, in the gingival fibroblasts pretreatment with IL-1β, cyclosporin A augmented bradykinin-stimulated PGE_2 release. RT-PCR analysis revealed that cyclosporin A increased the expression of cyclooxygenase-2 mRNA. The simultaneous treatment with cyclosporin A and IL-16 resulted in increased the expression of cyclooxygenase-2 mRNA compared to cells with IL-1β alone. To confirm the RT-PCR results, cyclooxygenase transcript levels were measured by quantitative real time RT-PCR. These real time RT-PCR data supported the RT-PCR results, confirming that cyclooxygenase-2 mRNA was up-regulated by cyclosporin A. Cyclosporin A could acts as an inflammatory mediator, likely by the induction of cyclooxygenase-2-mediated PGE_2 formation in human gingival fibroblasts. Taken together, our data suggest that induction of cyclooxygenase-2 and PGE_2 synthesis are enhanced by cyclosporine A where they may participate in cyclosporin A-induced gingival overgrowth.