HDAC4 contributes to IL-1-induced mPGES-1 expression in human synovial fibroblasts through up-regulation of Egr-1 transcriptional activity.
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.
Chabane
Nadir
N
Osteoarthritis Research Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Department of Medicine, Notre-Dame Hospital, University of Montreal, 1560 Sherbrooke Street East, Montreal, Quebec, Canada H2L 4M1.
Li
Xinfang
X
Fahmi
Hassan
H
D000107:Acetylation; D002478:Cells, Cultured; D004277:DNA, Single-Stranded / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D000071876:Prostaglandin-E Synthases; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013582:Synovial Fluid / Q000187:drug effects / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
C400152:DNA enzyme ED5; D004277:DNA, Single-Stranded; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D053583:Interleukin-1beta; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C400300:HDAC4 protein, human; D006655:Histone Deacetylases; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases