HDAC4 contributes to IL-1-induced mPGES-1 expression in human synovial fibroblasts through up-regulation of Egr-1 transcriptional activity.

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Chabane N, Li X, Fahmi H

HDAC4 contributes to IL-1-induced mPGES-1 expression in human synovial fibroblasts through up-regulation of Egr-1 transcriptional activity.

J Cell Biochem. 2009 Feb 15;106(3):453-63. doi: 10.1002/jcb.22027.

PubMed ID

19115247 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Valproic acid	Histone deacetylase (Protein Group)	Protein group	Humans	Unknown	Inhibitor	Details