Ristimäki A, Garfinkel S, Wessendorf J, Maciag T, Hla T
Department of Molecular Biology, Holland Laboratory, American Red Cross, Rockville, Maryland 20855.
J Biol Chem. 1994 Apr 22;269(16):11769-75.
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.
前列腺素由多种细胞类型产生，可调节多种病理生理过程。前列腺素的合成速率部分取决于前列腺素合成酶的水平，如环氧化酶（Cox），它是将花生四烯酸转化为前列腺素的限速酶。虽然已鉴定出两种Cox基因，但Cox-2很独特，因为它在包括炎症在内的细胞激活过程中会被高度诱导。我们研究了白细胞介素-1α（IL-1α），一种促炎细胞因子，其部分作用是通过诱导前列腺素的合成来实现的，对人细胞系（ECV304）中Cox-2表达的影响，并证明IL-1α可诱导Cox-2 mRNA以及功能性酶的表达持续增加。三种机制不同的翻译抑制剂刺激了Cox-2 mRNA的表达，并增强了IL-1α的作用。此外，IL-1α诱导Cox-2转录迅速但短暂的激活，并且在没有转录的情况下，延长了Cox-2 mRNA的半衰期。总之，这些数据表明转录后机制在Cox-2 mRNA的持续诱导中很重要，并且IL-1α可能会增加Cox-2转录本的稳定性。
