Induction of cyclooxygenase-2 by interleukin-1 alpha. Evidence for post-transcriptional regulation.
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. We have studied the effect of interleukin-1 alpha (IL-1 alpha), 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-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 Cox-2 mRNA and potentiated the effect of IL-1 alpha. Furthermore, IL-1 alpha 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-1 alpha may increase the stability of the Cox-2 transcript.
Ristimäki
A
A
Department of Molecular Biology, Holland Laboratory, American Red Cross, Rockville, Maryland 20855.
Garfinkel
S
S
Wessendorf
J
J
Maciag
T
T
Hla
T
T
D001483:Base Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D017931:DNA Primers; D003609:Dactinomycin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000201:enzymology*; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011453:Prostaglandins / Q000096:biosynthesis; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014471:Umbilical Veins
D017931:DNA Primers; D007375:Interleukin-1; D011453:Prostaglandins; D012333:RNA, Messenger; D003609:Dactinomycin; D011451:Prostaglandin-Endoperoxide Synthases; D013755:Tetradecanoylphorbol Acetate