The prostaglandin H synthases (PGHS) catalyze the conversion of arachidonic acid to prostaglandin H2, the committed step in prostanoid synthesis. Two forms of PGHS exist, PGHS-1 (COX-1) and PGHS-2 (COX-2). The gene encoding the latter form is known to be inducible by a number of stimuli including several inflammatory mediators. Recent evidence indicates that the inducible cyclooxygenase may have both pro- and anti-inflammatory properties through the generation of different prostaglandins. Previous reports indicate that the transcription factor NF-κB can function upstream of COX-2 to control transcription of this gene and that the cyclopentenone prostaglandins can inhibit NF-κB activation via the inhibition of the IκB kinase. Thus, it is suggested that cyclopentenones feed back to inhibit continued nuclear accumulation of NF-κB. In this report we demonstrate COX-2 expression inhibits nuclear translocation of NF-κB, and we confirm that the cyclopentenone prostaglandins inhibit NF-κB. In addition, we show that prostaglandin E2 and its analogs promote the inherent transcriptional activity of the p65/RelA subunit of NF-κB in a manner independent of induced nuclear accumulation. Consistent with this evidence, prostaglandin E2 strongly synergizes with the inflammatory cytokine tumor necrosis factor-α to promote NF-κB-dependent transcription and gene expression. The data provide a molecular rationale to explain both the pro-and anti-inflammatory nature of COX-2
