Analyses of prostaglandin E synthases that represent a potential target for novel anti-inflammatory drugs

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This study aims to clarify the functional aspects of three PGE_2 synthases (mPGES-1, mPGES-2 and cPGES) both in vitro and in vivo. In cell culture studies, mPGES-1, a stimulus-inducible, perinuclear enzyme, shows preferential functional coupling with the inducible cyclooxygenase (COX) isozyme, COX-2, to produce PGE_2. mPGES-2, a constitutive enzyme that is initially expressed as a Golgi membrane-associated protein and then released into the cytoplasm after proteolytic removal of the N-terminal hydrophobic domain, is coupled with both constitutive COX-1 and inducible COX-2. cPGES is a cytosolic, constitutive enzyme, and its association with Hsp90 and concomitant phsophorylation by casein kinase-2, an Hsp90 client protein, following Ca^<2+>-evoked stimuli eventually leads to a temporal COX-1-dependent PGE_2 generation. Whereas mPGES-1-deficient mice are normally born, grow and are fertile under normal housing condition, they exhibit reduced nociceptive response, inflammatory granulation … More and arthritis, and tumor growth and metastasis relative to replicate wild-type mice, implying the role of mPGES-1-derived PGE_2 in pain, inflammation and cancer. In contrast, there is an exacerbation of inflammatory bowel disease in mPGES-1-null mice compared with that in wild-type littermates, suggesting an additional contribution of mPGES-1 to the production of the gastrointestinal tissue-protective PGE_2. Thus, even though putative chemicals that specifically inhibit mPGES-1 might be useful as anti-nociceptive, inflammatory, and cancer drugs, some adverse side-effects such as gastrointestinal ulcer should be taken into consideration. Mice deficient in cPGES are perinatal lethal. Some developmental defects are found in several tissues of cPGES-null mice such as skin and lung, in which PGE_2 levels are markedly decreased. In contrast, PGE_2 levels in tissues seemingly unaffected by cPGES knockout, such as heart and liver, are similar between cPGES-null and wild-type mice. However, no such abnormalities have been reported for mice deficient in upstream PGE_2-biosynthetic enzymes or PGE_2 receptors, suggesting that the severe phenotypes occurred in cPGES-deficient mice might result from the lack of some unique function(s), rather than the PGE_2-synthetic function, of cPGES. Less