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Interferon-gamma suppresses cyclooxygenase-2 promoter activity by inhibiting C-Jun and C/EBPbeta binding
Wu-Guo Deng1, Alberto J Montero, Kenneth K Wu
1University of Texas Health Science Center, Houston, TX 77030-1503, USA.
Objective:
Cyclooxygenase-2 (COX-2) and interferon gamma (IFNgamma) are overexpressed in vascular inflammatory and atherosclerotic lesions. We postulated that IFNgamma suppresses COX-2 expression at the transcriptional level.
Methods And Results:
The effect of IFNgamma on COX-2 expression was evaluated in several types of human cells stimulated with phorbol 12-myristate 13-acetate (PMA), interleukin (IL)-1beta, or tumor necrosis factor (TNF) alpha. IFNgamma 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/EBPbeta), or NF-kappaB to their respective regulatory elements on COX-2 promoter. IFNgamma blocked C-Jun and C/EBPbeta but not C-Fos or p50 NF-kappaB binding as determined by in vitro binding assays and chromatin immunoprecipitation assay. p300 binding to COX-2 promoter was inhibited by IFNgamma in a manner comparable to C-Jun and C/EBPbeta binding.
Conclusions:
IFNgamma suppresses proinflammatory mediator-induced COX-2 transcription by selective inhibition of C-Jun and C/EBPbeta DNA binding activity and p300 recruitment in human cells. Because IFNgamma is coexpressed with COX-2 in vascular lesions, it may play a role in controlling COX-2-mediated inflammatory changes.
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