Regulation of prostaglandin E synthases: Effects of siRNA-mediated inhibition of microsomal prostaglandin E synthase-1
- 作者：Tove Bå ; ge ; Thomas Modé ; er ; Tomomi Kawakami ; Hernan Concha Quezada ; Tü ; lay Yucel-Lindberg
- 关键词：Prostaglandin E synthase ; siRNA ; Prostaglandin E2 ; COX-2 ; MK-886 ; Gingival fibroblast
- 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
- 出版年：2007
- 期刊代码：20_01674889
- 类别：bio
- 出版时间：October 2007
- 卷：1773
- 期：10
- 页码：1589-1598
- 文件大小：932 K
摘要
Prostaglandin E2 (PGE2) is a key mediator involved in several inflammatory conditions. In this study, we investigated the expression and regulation of the terminal PGE2 synthesizing enzyme prostaglandin E synthases (mPGES-1, mPGES-2 and cPGES) in gingival fibroblasts stimulated with pro-inflammatory cytokines. We used siRNA knockdown of mPGES-1 to elucidate the impact of mPGES-1 inhibition on mPGES-2 and cPGES expression, as well as on PGE2 production. The cytokines TNFα and IL-1β increased protein expression and activity of mPGES-1, accompanied by increased COX-2 expression and PGE2 production. The isoenzymes mPGES-2 and cPGES, constitutively expressed at mRNA and protein levels, were unaffected by the pro-inflammatory cytokines. We show for the first time that treatment with mPGES-1 siRNA down-regulated the cytokine-induced mPGES-1 protein expression and activity. Interestingly, mPGES-1 siRNA did not affect the cytokine-stimulated PGE2 production, whereas PGF2α levels were enhanced. Neither mPGES-2 nor cPGES expression was affected by siRNA silencing of mPGES-1. Dexamethasone and MK-886 both inhibited the cytokine-induced mPGES-1 expression while mPGES-2 and cPGES expression remained unaffected. In conclusion, mPGES-1 siRNA down-regulates mPGES-1 expression, and neither mPGES-2 nor cPGES substituted for mPGES-1 in a knockdown setting in gingival fibroblasts. Moreover, mPGES-1 siRNA did not affect PGE2 levels, whereas PGF2α increased, suggesting a compensatory pathway of PGE2 synthesis when mPGES-1 is knocked down.