Down-regulation of cytokine-induced cyclo-oxygenase-2 transcript isoforms by dexamethasone: evidence for post-transcriptional regulation.
The immediate-early cyclo-oxygenase-2 (Cox-2) gene encodes an inducible prostaglandin synthase enzyme that has been implicated in inflammatory and proliferative diseases. We have shown that the inflammatory cytokine interleukin-1 (IL-1) induces the Cox-2 gene in a sustained manner and that post-transcriptional mRNA stabilization is an important even [Ristimäki, Garfinkel, Wessendorf, Maciag and Hla (1994) J. Biol. Chem. 269, 11769-11775]. The anti-inflammatory glucocorticoid dexamethasone potently down-regulates IL-1-induced Cox-2 mRNA expression. Kinetic studies suggest that antagonism of IL-1-induced mRNA stabilization is, at least in part, responsible for the suppression of Cox-2 mRNA. The Cox-2 gene produces two major transcript isoforms, namely Cox-2(4.6) (4.6 kb) and Cox-2(2.8) (2.8 kb), which are derived by alternative polyadenylation in the 3'-untranslated region (UTR). In response to dexamethasone, the short Cox-2(2.8) transcript isoform, which lacks a highly conserved AU-rich region, decays with a longer half-life than the Cox-2(4.6) isoform. Furthermore, heterologous expression of the hybrid Cox-1 open reading frame and the Cox-2 3'-UTR results in the accumulation of high levels of the short isoform and lower levels of the long isoform. These data suggest that multiple elements in the 3'-UTR of the Cox-2 gene are involved in the determination of the differential mRNA stabilities of Cox-2 transcript isoforms. Because dexamethasone destabilizes the Cox-2 transcript, and because the decay of Cox-2 transcript isoforms induced by dexamethasone occurs with different half-lives, post-transcriptional mRNA destabilization may be an important mechanism in the action of anti-inflammatory glucocorticoids.
Ristimäki
A
A
Department of Molecular Biology, Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.
Narko
K
K
Hla
T
T
D001483:Base Sequence; D015152:Blotting, Northern; D015139:Blotting, Southern; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016914:Ribonuclease H / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D005938:Glucocorticoids; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D003609:Dactinomycin; D004004:Dichlororibofuranosylbenzimidazole; D003907:Dexamethasone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D016914:Ribonuclease H