Induction of cyclooxygenase-2 by interleukin-1 alpha. Evidence for post-transcriptional regulation.

Abstract

Prostanoids, produced by diverse cell types, modulate a variety of pathophysiological processes.The rate of prostanoid synthesis is determined, in part, by the levels of prostanoid-synthetic enzymes, such as cyclooxygenase (Cox), a rate-limiting enzyme in the conversion of arachidonic acid to prostanoids.While two Cox genes have been identified, Cox-2 is unique because it is highly induced in response to cell activation processes including inflammation.W e have studied the effect of interleukin-la (IL-la), a proinflammatory cytokine that facilitates its actions in part by inducing the synthesis of prostanoids, on the expression of Cox-2 in a human cell line (ECV304) and demonstrated that IL-la induces a sustained increase in the expression of the Cox-2 mRNA as well as the functional enzyme.Three mechanistically distinct inhibitors of translation stimulated the expression of the Cox-2 mRNA and potentiated the effect of IL-la.Furthermore, IL-la induced rapid but transient activation of Cox-2 transcription and, in the absence of transcription, prolonged the half-life of the Cox-2 mRNA.Together, these data suggest that post-transcriptional mechanisms are important in the sustained induction of the Cox-2 mRNA and that IL-la may increase the stability of the Cox-2 transcript.Prostaglandins, thromboxane, and prostacyclin, collectively known as prostanoids, are metabolites of arachidonic acid and are synthesized and released by most human tissues and cell types (reviewed by Needleman et al. (1986)).Phospholipase (PLY 4 initiates prostanoid synthesis by releasing arachidonicacid from membrane fatty acids, and once released arachidonic acid is oxidized to prostaglandin (PG) G, by cyclooxygenase (Cox; PG-endoperoxide G/H synthase) and reduced to PGH, by the peroxidase activity of the same enzyme.PGH, is then converted to biologically active prostanoids by tissue-specific isomerases.Due to their unstable nature, prostanoids usually act in an autocrine or paracrine manner, and continuous synthesis is needed to facilitate their diverse biological effects.