Differential regulation of prostaglandin E biosynthesis by interferon-gamma in colonic epithelial cells

Br J Pharmacol. 2004 Apr;141(7):1091-7. doi: 10.1038/sj.bjp.0705719. Epub 2004 Mar 15.

Abstract

1. Cyclooxygenase (COX)-2 expression and activity in response to pro-inflammatory cytokines TNF alpha and IFN gamma was evaluated in the colonic epithelial cell line HT29 and the airway epithelial cell line A549. 2. TNF alpha induced concentration- and time-dependent upregulation of COX-2 mRNA, protein and prostaglandin (PG)E(2) synthesis. 3. Co-stimulation of TNF alpha with IFN gamma resulted in reduced COX-2 mRNA and protein expression. 4. IFN gamma had no effect on the stability of TNF alpha-induced COX-2 mRNA. 5. TNF alpha-induced PGE(2) biosynthesis was significantly enhanced by the simultaneous addition of IFN gamma and was COX-2 dependent. 6. The combination of IFN gamma and TNF alpha induced the microsomal prostaglandin E synthase (mPGES), comensurate with the enhanced PGE(2) synthesis. 7. These results suggest that, in terms of PGE(2) biosynthesis, IFN gamma plays a negative regulatory role at the level of COX-2 expression and a positive regulatory role at the level of mPGES expression. This may have important implications for the clinical use of IFN gamma in inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caco-2 Cells
  • Colon / drug effects
  • Colon / metabolism*
  • Colon / pathology
  • Cyclooxygenase Inhibitors / metabolism
  • Dactinomycin / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Evaluation Studies as Topic
  • HT29 Cells
  • Humans
  • Interferon-alpha / metabolism
  • Interferon-alpha / pharmacology
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / metabolism
  • Interferon-gamma / pharmacology*
  • Intramolecular Oxidoreductases / genetics
  • Intramolecular Oxidoreductases / metabolism
  • Mice
  • Microsomes / enzymology
  • Prostaglandin-E Synthases
  • Prostaglandins E / biosynthesis*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Tumor Necrosis Factor-alpha / drug effects
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • Up-Regulation

Substances

  • Cyclooxygenase Inhibitors
  • Interferon-alpha
  • Prostaglandins E
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Dactinomycin
  • Interferon-gamma
  • Intramolecular Oxidoreductases
  • Prostaglandin-E Synthases