Impaired Inflammatory and Pain Responses in Mice Lacking an Inducible Prostaglandin E Synthase

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 15; pp. 9044 - 9049
• Main Authors: Trebino, Catherine E., Stock, Jeffrey L., Gibbons, Colleen P., Naiman, Brian M., Wachtmann, Timothy S., Umland, John P., Pandher, Karamjeet, Lapointe, Jean-Martin, Saha, Sipra, Roach, Marsha L., Carter, Demetrius, Thomas, Nathalie A., Durtschi, Becky A., McNeish, John D., Hambor, John E., Jakobsson, Per-Johan, Carty, Thomas J., Perez, Jose R., Audoly, Laurent P.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22.07.2003; National Acad Sciences
• Series: From the Cover
• Subjects: Animals; Arthritis; Arthritis, Experimental - etiology; Arthritis, Experimental - pathology; Arthritis, Experimental - physiopathology; Arthritis, Rheumatoid - etiology; Arthritis, Rheumatoid - pathology; Arthritis, Rheumatoid - physiopathology; Biological Sciences; Collagens; Dinoprostone - biosynthesis; Disease models; Edema; Female; Humans; Hypersensitivity, Delayed; Inflammation; Inflammation - physiopathology; Inflammation Mediators - metabolism; Intramolecular Oxidoreductases - deficiency; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - physiology; Joints; Macrophages; Macrophages - enzymology; Male; Medicin och hälsovetenskap; Metabolic diseases; Mice; Mice, Inbred DBA; Mice, Knockout; Pain - drug therapy; Pain - physiopathology; Pain management; Prostaglandin-E Synthases; Prostaglandins; Rodents
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1332766100

Prostaglandin (PG)E2is a potent mediator of pain and inflammation, and high levels of this lipid mediator are observed in numerous disease states. The inhibition of PGE2production 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 PGH2into 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 PGE2that 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.