Valproic Acid Suppresses Interleukin-1β-induced Microsomal Prostaglandin E2 Synthase-1 Expression in Chondrocytes Through Upregulation of NAB1

Objective. Microsomal prostaglandin E-2 synthase-1 (mPGES-1) catalyzes the terminal step in the biosynthesis of PGE(2). Early growth response factor-1 (Egr-1) is a key transcription factor in the regulation of mPGES-1, and its activity is negatively regulated by the corepressor NGFI-A-binding protein-1 (NAB1). We examined the effects of valproic acid (VA), a histone deacetylase inhibitor, on interleukin 1 beta (IL-1 beta)-induced mPGES-1 expression in human chondrocytes, and evaluated the roles of Egr-1 and NAB1 in these effects. Methods. Chondrocytes were stimulated with IL-1 in the absence or presence of VA, and the level of mPGES-1 protein and mRNA expression were evaluated using Western blotting and real-time reverse-transcription polymerase chain reaction (PCR), respectively. mPGES-1 promoter activity was analyzed in transient transfection experiments. Egr-1 and NAB1 recruitment to the mPGES-1 promoter was evaluated using chromatin immunoprecipitation assays. Small interfering RNA (siRNA) approaches were used to silence NAB1 expression. Results. VA dose-dependently suppressed IL-1-induced mPGES-1 protein and mRNA expression as well as its promoter activation. Treatment with VA did not alter IL-1-induced Egr-1 expression, or its recruitment to the mPGES-1 promoter, but prevented its transcriptional activity. The suppressive effect of VA requires de 1701;0 protein synthesis. VA induced the expression of NAB1, and its recruitment to the mPGES-1 promoter, suggesting. that NAB I may mediate the suppressive effect of VA. Indeed, NAB1 silencing with siRNA blocked VA-mediated suppression of IL-1-induced mPGES-1 expression. Conclusion. VA inhibited IL-1-induced mPGES-1 expression in chondrocytes. The suppressive effect of VA was not due to reduced expression or recruitment of Egr-1 to the mPGES-1 promoter and involved upregulation of NAB I. (First Release Jan 15 2011: J Rheumatol 2011;38:492-502; doi:10.3899/jrheum.100907)