Microsomal postaglandin (PG) E synthase (mPGES)-1 is an inducible enzyme that acts downstream of cyclooxygenase (COX) and specifically catalyzes the conversion of prostaglandin (PG)H 2 to PGE 2 , 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 PGE 2 production in Het and null MEFs under basal conditions and after stimulation with interleukin (IL)-1ß, suggesting that mPGES-1 is critically important for PGE 2 production. Furthermore, we show that mPGES-1 gene deletion results in diversion of prostanoid production from PGE 2 to 6-keto PGF 1α (the stable metabolic product of PGI 2 ; 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 PGE 2 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.—Kapoor, M., Kojima, F., Qian, M., Yang, L., and Crofford, L. J. Shunting of prostanoid biosynthesis in microsomal prostaglandin E synthase-1 null embryo fibroblasts: regulatory effects on inducible nitric oxide synthase expression and nitrite synthesis.
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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, Mohit; Kojima, Fumiaki; Qian, Min; Yang, Lihua; Crofford, Leslie J.
Follow The FASEB Journal
, Volume 20 (13): 2387
Fed of American Socs for Experimental Biology – Nov 1, 2006
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