Prostanoids and PGE2 in particular have been long viewed as one of the major mediators of inflammation in arthritis. However, experimental data indicate that PGE2 can serve both pro- and anti-inflammatory functions. We have previously shown (Kojima et al., J. Immunol. 180 (2008) 8361-8368) that microsomal prostaglandin E synthase-1 (mPGES-1) deletion, which regulates PGE2 production, resulted in the suppression of collagen-induced arthritis (CIA) in mice. This suppression was attributable, at least in part, to the impaired generation of type II collagen autoantibodies. In order to examine the function of mPGES-1 and PGE2 in a non-autoimmune form of arthritis, we used the collagen antibody-induced arthritis (CAIA) model in mice deficient in mPGES-1, thereby bypassing the engagement of the adaptive immune response in arthritis development. Here we report that mPGES-1 deletion significantly increased CAIA disease severity. The latter was associated with a significant (~3.6) upregulation of neutrophil, but not macrophage, recruitment to the inflamed joints. The lipidomic analysis of the arthritic mouse paws by quantitative liquid chromatography/tandem mass-spectrometry (LC/MS/MS) revealed a dramatic (~59-fold) reduction of PGE2 at the peak of arthritis. Altogether, this study highlights mPGES-1 and its product PGE2 as important negative regulators of neutrophil-mediated inflammation and suggests that specific mPGES-1 inhibitors may have differential effects on different types of inflammation. Furthermore, neutrophil-mediated diseases could be exacerbated by inhibition of mPGES-1.
Keywords: (±)14(15)-epoxy-5Z,8Z,11Z-eicosatrienoic acid; (±)14,15-dihydroxy-5Z,8Z,11Z-eicosatrienoic acid; (±)9(10)-epoxy-12Z-octadecenoic acid; (±)9,10-dihydroxy-12Z-octadecenoic acid; 11-HETE; 11-hydroxyeicosatetraenoic acid; 14,15-DiHETrE; 14,15-EpETrE; 15-HETE; 15-hydroxyeicosatetraenoic acid; 5-HETE; 5-hydroxyeicosatetraenoic acid; 9,10-DiHOME; 9,10-EpOME; 9-HETE; 9-hydroxyeicosatetraenoic acid; ARA; Arthritis; IL-6; Inflammation; LC/MS/MS; MPO; PGD2; PGE2; PGF2a; Prostaglandin; RA; arachidonic acid; interleukin 6; liquid chromatography/tandem mass spectrometry; mPGES-1; myeloperoxidase; prostaglandin D2; prostaglandin E2; prostaglandin F2a; rheumatoid arthritis; rheumatoid arthritis.
© 2013 Published by Elsevier Ltd.