INDUCTION OF CYCLOOXYGENASE-2 BY INTERLEUKIN-1-ALPHA - EVIDENCE FOR POSTTRANSCRIPTIONAL REGULATION

Prostanoids, produced by diverse cell types, modulate a variety of pat hophysiological processes. The rate of prostanoid synthesis is determi ned, in part, by the levels of prostanoid-synthetic enzymes, such as c yclooxygenase (Cox), a rate-limiting enzyme in the conversion of arach idonic acid to prostanoids. While two Cox genes have been identified, Cox-2 is unique because it is highly induced in response to cell activ ation processes including inflammation. We have studied the effect of interleukin-1 alpha (IL-1 alpha), a proinflammatory cytokine that faci litates its actions in part by inducing the synthesis of prostanoids, on the expression of Cox-2 in a human cell line (ECV304) and demonstra ted that IL-1 alpha 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 C ox-2 mRNA and potentiated the effect of IL-1 alpha. Furthermore, IL-1 alpha induced rapid but transient activation of Cox-2 transcription an d, in the absence of transcription, prolonged the half-life of the Cox -2 mRNA Together, these data suggest that post-transcriptional mechani sms are important in the sustained induction of the Cox-2 mRNA and tha t IL-1 alpha may increase the stability of the Cox-2 transcript.