Regulation of prostaglandin E-2 biosynthesis by inducible membrane-associated prostaglandin E-2 synthase that acts in concert with cyclooxygenase-2

Here we report the molecular identification of membrane-bound glutathione ( GSH)-dependent prostaglandin (PG) E-2 synthase (mPGES), a terminal enzyme o f the cyclooxygenase (COX)-2-mediated PGE(2) biosynthetic pathway. The acti vity of mPGES was increased markedly in macrophages and osteoblasts followi ng proinflammatory stimuli. cDNA for mouse and rat mPGESs encoded functiona l proteins that showed high homology with the human ortholog (microsomal gl utathione S-transferase-like 1). mPGES expression was markedly induced by p roinflammatory stimuli in various tissues and cells and was down-regulated by dexamethasone, accompanied by changes in COX-2 expression and delayed PG E(2) generation. Arg(110), a residue well conserved in the microsomal GSH S -transferase family, was essential for catalytic function, mPGES was functi onally coupled with COX-2 in marked preference to COX-1, particularly when the supply of arachidonic acid was limited. Increased supply of arachidonic acid by explosive activation of cytosolic phospholipase A(2) allowed mPGES to be coupled with COX-1. mPGES colocalized with both COX isozymes in the perinuclear envelope. Moreover, cells stably cotransfected with COX-2 and m PGES grew faster, were highly aggregated, and exhibited aberrant morphology . Thus, COX-2 and mPGES are essential components for delayed PGE(2) biosynt hesis, which may be linked to inflammation, fever, osteogenesis, and even c ancer.