Microsomal prostaglandin E synthase-1 genetic deletion results in reduced incidence and severity of collagen-induced arthritis associated with a marked reduction of anti-collagen antibodies (130.47)

Abstract

Abstract Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme that acts downstream of cyclooxygenase and specifically catalyzes the conversion of prostaglandin (PG)H2 to PGE2, most prominently in inflammatory conditions. However, the role of mPGES-1 in the immune response has not yet been full elucidated. In this study, we demonstrate the effect of genetic deletion of mPGES-1 on initiating immune responses as well as clinical arthritis development in bovine collagen-induced arthritis (CIA), a well established model to study pathogenic mechanisms relevant to rheumatoid arthritis. mPGES-1 null and heterozygous mice exhibited decreased paw edema, arthritis severity and incidence compared to wild-type mice in a gene dose-dependent manner. Histopathological changes further showed a significant reduction in lining hyperplasia and tissue destruction in mPGES-1 null mice compared to their wild-type littermates. In addition, mPGES-1 genetic deletion showed attenuated mechanical allodynia in a gene dose-dependent manner. The reduction of inflammatory features observed in mPGES-1 null mice were associated with significantly lower levels of IgG including IgG1, IgG2a, IgG2b, IgG2c and IgG3 against type II collagen (CII). These results suggest that deficiency of mPGES-1 inhibits the development of CIA, at least in part, by blocking development of the anti-CII antibody response. Grant Support: Arthritis Foundation Biomedical Sciences Grant and NIH/NIAMS AR49010.