Regulation of cyclooxygenase-2 expression by cyclic AMP.
Prostaglandins (PG) regulate many biological processes, among others inflammatory reactions. Cyclooxygenases-1 and -2 (COX-1 and COX-2) catalyse PG synthesis. Since this step is rate limiting, the regulation of COX expression is of critical importance to PG biology. Contrary to COX-1, which is constitutively expressed, COX-2 expression is subject to regulation. For example, COX-2 levels are increased in inflammatory reactions. Many signalling pathways can regulate COX-2 expression, not least those involving receptors for COX products themselves. Analysis of the intracellular signal transducers involved reveals a crucial role for cAMP, albeit as a modulator rather than direct inducer. Indeed, the influence of cAMP on COX-2 expression is complex and dependent on the cell type and cellular environment. This review aims to summarise various topics related to cAMP-dependent COX-2 expression. Firstly, the main aspects of COX-2 regulation are briefly considered. Secondly, the molecular basis for COX-2 gene (post)-transcriptional regulation is reviewed. Lastly, a detailed overview of the effects of cAMP-dependent signalling on COX-2 mRNA and protein expression in various human and rodent cells is provided. There is a large number of marketed, clinical and preclinical concepts promoting the elevation of intracellular cAMP levels for therapeutic purposes (e.g., beta(2)-agonists, PG receptor agonists, phosphodiesterase inhibitors). In this respect, the role of cAMP in the regulation of COX-2 expression, especially the human enzyme, is of significant clinical importance.
Klein
Thomas
T
Department of Biochemistry, ALTANA Pharma, D-78467 Konstanz, Germany.
Shephard
Pierre
P
Kleinert
Hartmut
H
Kömhoff
Martin
M
D000818:Animals; D000242:Cyclic AMP / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects
D000242:Cyclic AMP; D051546:Cyclooxygenase 2