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

Arterioscler Thromb Vasc Biol. 2007 Aug;27(8):1752-9. doi: 10.1161/ATVBAHA.107.144352. Epub 2007 Jun 7.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Cells, Cultured
  • Cyclooxygenase 2 / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Endothelial Cells / cytology
  • Enhancer Elements, Genetic
  • Fibroblasts / cytology
  • Gene Expression Regulation
  • Humans
  • Interferon-gamma / metabolism*
  • Male
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Sensitivity and Specificity

Substances

  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins c-jun
  • Interferon-gamma
  • Cyclooxygenase 2