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.