Abstract
Microsomal prostaglandin E synthase‐1 (mPGES‐1) catalyzes the terminal step in the biosynthesis of PGE~2~, which contributes to many physiopathological processes. We show here that inhibitors of histone deacetylase (HDAC) activity, trichostatin A (TSA), butyric acid (BA), and valproic acid (BA) prevented IL‐1‐induced mPGES‐1 protein expression in human synovial fibroblasts. TSA also inhibited IL‐1‐induced mPGES‐1 mRNA expression and promoter activation. Overexpression of HDAC4, but not of HDAC1, 2, 3, 5, or 6 enhanced, whereas HDAC4 silencing with small interfering RNA (siRNA) reduced, IL‐1‐induced mPGES‐1 promoter activation, implying that HDAC4 contributes to mPGES‐1 gene expression. Consistently, IL‐1‐induced mPGES‐1 protein expression was prevented by siRNA for HDAC4. We also demonstrate that IL‐1‐induced HDAC4 recruitment to the mPGES‐1 promoter. This recruitment was not accompanied by deacetylation of histones H3 and H4, suggesting that HDAC4 contributes to mPGES‐1 induction independently of local deacetylation of histones H3 and H4. We then investigated whether HDAC4 regulates mPGES‐1 expression by modulating the activity of Egr‐1, a key transcription factor in IL‐1‐induced mPGES‐1 expression. We found that HDAC4 overexpression enhances, whereas HDAC4 knockdown by siRNA reduces Egr‐1‐mediated activation of the mPGES‐1 promoter. Together these data indicate that HDAC4 contributes to transcriptional induction of mPGES‐1 by IL‐1 through a mechanism involving up‐regulation of Egr‐1 transcriptional activity. J. Cell. Biochem. 106: 453–463, 2009. © 2008 Wiley‐Liss, Inc.