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 event [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-24.6 (4.6 kb) and Cox-22.8 (2.8 kb), which are derived by alternative polyadenylation in the 3´-untranslated region (UTR). In response to dexamethasone, the short Cox-22.8 transcript isoform, which lacks a highly conserved AU-rich region, decays with a longer half-life than the Cox-24.6 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.
Down-regulation of cytokine-induced cyclo-oxygenase-2 transcript isoforms by dexamethasone: evidence for post-transcriptional regulation
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Ari RISTIMÄKI, Kirsi NARKO, Timothy HLA; Down-regulation of cytokine-induced cyclo-oxygenase-2 transcript isoforms by dexamethasone: evidence for post-transcriptional regulation. Biochem J 15 August 1996; 318 (1): 325–331. doi: https://doi.org/10.1042/bj3180325
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