MPGES-1 as a novel target for arthritis.

Abstract

Prostaglandin E2 (PGE2) is by far the major prostanoid synthesized in the joint and plays an important role in inflammation and pathogenesis of arthritis. Moreover, increased levels of PGE2 have been detected in serum and synovial fluids from arthritic patients. Little was known about the enzyme(s) involved in the isomerization of PGH2 into PGE2 synthesis until recent identification of PGE synthase (PGES). Several isoforms were characterized, among which microsomal PGES-1 (mPGES-1) has received much attention, because this enzyme is inducible and functionally linked with cyclooxygenase-2. This review focuses on recent findings regarding the regulation of mPGES-1 expression and the possible role of this enzyme in arthritis. Various in vitro and in vivo studies demonstrated that proinflammatory stimuli, such as interleukin-1beta and tumor necrosis factor-alpha upregulate the expression of mPGES-1 at the protein and mRNA level. Promoter analysis indicates that the transcription factor Egr-1 is involved in the positive regulation of mPGES-1. Studies from mPGES-1-deficient mice and animal models of inflammatory arthritis strongly suggest a role of mPGES-1 in the production of PGE2 and the pathogenesis of arthritis. This article reviews the regulation of mPGES-1 expression and provides evidence for a role of mPGES-1 in inducible PGE2 production and arthritis. Future studies using selective inhibitors of mPGES-1 activity or expression would clarify the role of this enzyme in arthritis.