Positive and negative regulation of NF-kappa B by COX-2-Roles of differentprostaglandins

The prostaglandin H synthases (PGHS) catalyze the conversion of arachidonic acid to prostaglandin H-2, 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 s everal 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-kappaB can function upstream of COX-2 to contr ol transcription of this gene and that the cyclopentenone prostaglandins ca n inhibit NF-kappaB activation via the inhibition of the I kappaB kinase. T hus, it is suggested that cyclopentenones feed back to inhibit continued nu clear accumulation of NF-kappaB. In this report we demonstrate COX-2 expres sion inhibits nuclear translocation of NF-kappaB, and we confirm that the c yclopentenone prostaglandins inhibit NF-kappaB. In addition, we show that p rostaglandin E-2 and its analogs promote the inherent transcriptional activ ity of the p65/RelA subunit of NF-kappaB in a manner independent of induced nuclear accumulation. Consistent with this evidence, prostaglandin E2 stro ngly synergizes with the inflammatory cytokine tumor necrosis factor-a to p romote NF-kappaB-dependent transcription and gene expression. The data prov ide a molecular rationale to explain both the pro- and anti-inflammatory na ture of COX-2.