Novel regulation of cyclooxygenase-2 expression and prostaglandin E2 production by IFN-gamma in human macrophages.
Cyclooxygenase-2 (COX-2) is the inducible enzyme in macrophages responsible for high output PG production during inflammation and immune responses. Although several stimuli are known to regulate COX-2, the molecular mechanisms modulating its expression by the cytokine network are poorly understood. As IFN-gamma priming is essential for macrophage accessory and effector cell functions, we investigated the effect of IFN-gamma on COX-2 expression in U937 human macrophages stimulated with IL-1beta. A dose- and time-dependent increase in COX-2 mRNA and protein expression was evoked by IL-1beta, whereas the levels of COX-1, the constitutively expressed isoform, remained unaltered. Interestingly, IFN-gamma-primed cells showed 40 to 60% lower levels of COX-2 mRNA, protein expression, and PGE2 production as compared with nonprimed cells. IFN-gamma-priming (50-500 U/ml) down-regulated COX-2 expression in a time- and dose-dependent fashion. Furthermore, IFN-gamma inhibited COX-2 gene transcription in response to IL-1beta but not to LPS. In contrast, the rate of decay of COX-2 transcripts in nonprimed and primed macrophages was similar (t1/2 = 3.2 h). The down-regulatory effect of IFN-gamma on IL-1beta-induced COX-2 expression was abrogated with cycloheximide. These results highlight a novel mechanism of COX-2 regulation by IFN-gamma at the transcriptional level, which may affect the outcome of inflammatory and immune conditions.
Barrios-Rodiles
M
M
Institute of Parasitology, McGill University, Ste. Anne de Bellevue, Quebec, Canada.
Chadee
K
K
D002460:Cell Line; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis*; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D004790:Enzyme Induction / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology
D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone