Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase

CE Trebino, JL Stock, CP Gibbons… - Proceedings of the …, 2003 - National Acad Sciences
CE Trebino, JL Stock, CP Gibbons, BM Naiman, TS Wachtmann, JP Umland, K Pandher…
Proceedings of the National Academy of Sciences, 2003National Acad Sciences
Prostaglandin (PG) E2 is a potent mediator of pain and inflammation, and high levels of this
lipid mediator are observed in numerous disease states. The inhibition of PGE2 production
to control pain and to treat diseases such as rheumatoid arthritis to date has depended on
nonsteroidal antiinflammatory agents such as aspirin. However, these agents inhibit the
synthesis of all prostanoids. To produce biologically active PGE2, PGE synthases catalyze
the isomerization of PGH2 into PGE2. Recently, several PGE synthases have been identified …
Prostaglandin (PG)E2 is a potent mediator of pain and inflammation, and high levels of this lipid mediator are observed in numerous disease states. The inhibition of PGE2 production to control pain and to treat diseases such as rheumatoid arthritis to date has depended on nonsteroidal antiinflammatory agents such as aspirin. However, these agents inhibit the synthesis of all prostanoids. To produce biologically active PGE2, PGE synthases catalyze the isomerization of PGH2 into PGE2. Recently, several PGE synthases have been identified and cloned, but their role in inflammation is not clear. To study the physiological role of the individual PGE synthases, we have generated by targeted homologous recombination a mouse line deficient in microsomal PGE synthase 1 (mPGES1) on the inbred DBA/1lacJ background. mPGES1-deficient (mPGES1-/-) mice are viable and fertile and develop normally compared with wild-type controls. However, mPGES1-/- mice displayed a marked reduction in inflammatory responses compared with mPGES1+/+ mice in multiple assays. Here, we identify mPGES1 as the PGE synthase that contributes to the pathogenesis of collagen-induced arthritis, a disease model of human rheumatoid arthritis. We also show that mPGES1 is responsible for the production of PGE2 that mediates acute pain during an inflammatory response. These findings suggest that mPGES1 provides a target for the treatment of inflammatory diseases and pain associated with inflammatory states.
National Acad Sciences