Interferon-gamma suppresses cyclooxygenase-2 promoter activity by inhibiting C-Jun and C/EBPbeta binding.
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.


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.
Deng
Wu-Guo
WG
University of Texas Health Science Center, Houston, TX 77030-1503, USA.
Montero
Alberto J
AJ
Wu
Kenneth K
KK
D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology; D004742:Enhancer Elements, Genetic; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008297:Male; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012680:Sensitivity and Specificity
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D016755:Proto-Oncogene Proteins c-jun; D007371:Interferon-gamma; D051546:Cyclooxygenase 2