Differential regulation of prostaglandin E biosynthesis by interferon-gamma in colonic epithelial cells.
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.
Wright
Karen L
KL
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY.
Weaver
Sean A
SA
Patel
Kajal
K
Coopman
Karen
K
Feeney
Mark
M
Kolios
George
G
Robertson
Duncan A F
DA
Ward
Stephen G
SG
D000818:Animals; D018938:Caco-2 Cells; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005069:Evaluation Studies as Topic; D019073:HT29 Cells; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008861:Microsomes / Q000201:enzymology; D000071876:Prostaglandin-E Synthases; D011458:Prostaglandins E / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation
D016861:Cyclooxygenase Inhibitors; D016898:Interferon-alpha; D011458:Prostaglandins E; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D007371:Interferon-gamma; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases