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Shunting of prostanoid biosynthesis in microsomal prostaglandin E synthase-1 null embryo fibroblasts: regulatory effects on inducible nitric oxide synthase expression and nitrite synthesis.

Kapoor M, Kojima F, Qian M, Yang L, Crofford LJ

Department of Internal Medicine, Rheumatology Division, Kentucky Clinic, University of Kentucky, Lexington, KY 40536-0284, USA.

Microsomal prostaglandin (PG) E synthase (mPGES)-1 is an inducible enzyme that acts downstream of cyclooxygenase (COX) and specifically catalyzes the conversion of prostaglandin (PG)H2 to PGE2, most prominently in inflammatory conditions. Specific inhibitors of mPGES-1 are not yet available, however, mice with genetic deletion of mPGES-1 have been generated that have given insight into the specific role of mPGES-1 in eicosanoid biosynthesis in vivo and in peritoneal macrophages. We created mouse embryo fibroblast (MEF) cell lines that would facilitate investigation of the effect of mPGES-1 genetic deletion on prostanoid biosynthesis in fibroblast lineage cells and its subsequent effect on the expression of inducible NOS (iNOS) and nitrite biosynthesis using cells derived from mPGES-1 wild-type (WT), heterozygous (Het), and null mice. The results show that genetic deletion of mPGES-1 results in a dramatic decrease in PGE2 production in Het and null MEFs under basal conditions and after stimulation with interleukin (IL)-1beta, suggesting that mPGES-1 is critically important for PGE2 production. Furthermore, we show that mPGES-1 gene deletion results in diversion of prostanoid production from PGE2 to 6-keto PGF1alpha (the stable metabolic product of PGI2; prostacyclin) in a gene dose-dependent manner in Het and null MEFs compared with their WT counterparts, suggesting a shunting phenomenon within the arachidonic acid (AA) metabolic pathway. In addition, we show that mPGES-1 gene deletion and subsequent decrease in PGE2 levels results in a differential induction profile of iNOS and nitrite levels (the stable breakdown product of nitric oxide (NO) in mPGES-1 WT MEFs compared with null MEFs. These results provide important information regarding the therapeutic potential for pharmacologic inhibition of mPGES-1 in inflammatory conditions.

Published 1 November 2006 in FASEB J, 20(13): 2387-9.
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