Interferon-γ suppresses cyclooxygenase-2 promoter activity by inhibiting C-jun and C/EBP β binding

Objective - Cyclooxygenase- 2 (COX-2) and interferon gamma ( IFN gamma) are overexpressed in vascular inflammatory and atherosclerotic lesions. We postulated that IFN gamma suppresses COX-2 expression at the transcriptional level. Methods and Results - The effect of IFN gamma on COX-2 expression was evaluated in several types of human cells stimulated with phorbol 12-myristate 13-acetate ( PMA), interleukin ( IL)-1 beta, or tumor necrosis factor ( TNF) alpha. IFN gamma concentration-dependently inhibited COX-2 proteins and promoter activities induced by PMA or cytokines in human fibroblasts and monocytic and endothelial cells. PMA and cytokines stimulate binding of C-Jun, C-Fos, CCAAT/enhancer binding protein beta (C/EBP beta), or NF-kappa B to their respective regulatory elements on COX-2 promoter. IFN gamma blocked C-Jun and C/EBP beta but not C-Fos or p50 NF-kappa B binding as determined by in vitro binding assays and chromatin immunoprecipitation assay. p300 binding to COX-2 promoter was inhibited by IFN gamma in a manner comparable to C-Jun and C/EBP beta binding. Conclusions - IFN gamma suppresses proinflammatory mediator-induced COX-2 transcription by selective inhibition of C-Jun and C/EBP beta DNA binding activity and p300 recruitment in human cells. Because IFN gamma is coexpressed with COX-2 in vascular lesions, it may play a role in controlling COX-2-mediated inflammatory changes.