Reduced Pain Hypersensitivity and Inflammation in Mice Lacking Microsomal Prostaglandin E Synthase-1

Abstract

We examined the in vivo role of membrane-bound prostaglandin E synthase (mPGES)-1, a terminal enzyme in the PGE 2 -biosynthetic pathway, using mPGES-1 knockout (KO) mice. Comparison of PGES activity in the membrane fraction of tissues from mPGES-1 KO and wild-type (WT) mice indicated that mPGES-1 accounted for the majority of lipopolysaccharide (LPS)-inducible PGES in WT mice. LPS-stimulated production of PGE 2 , but not other PGs, was impaired markedly in mPGES-1-null macrophages, although a low level of cyclooxygenase-2-dependent PGE 2 production still remained. Pain nociception, as assessed by the acetic acid writhing response, was reduced significantly in KO mice relative to WT mice. This phenotype was particularly evident when these mice were primed with LPS, where the stretching behavior and the peritoneal PGE 2 level of KO mice were far less than those of WT mice. Formation of inflammatory granulation tissue and attendant angiogenesis in the dorsum induced by subcutaneous implantation of a cotton thread were reduced significantly in KO mice compared with WT mice. Moreover, collagen antibody-induced arthritis, a model for human rheumatoid arthritis, was milder in KO mice than in WT mice. Collectively, our present results provide unequivocal evidence that mPGES-1 contributes to the formation of PGE 2 involved in pain hypersensitivity and inflammation.

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

“…Balb/c and C57BL6 mice were purchased from Saitama Experimental Animals Supply Co. Ltd. (Saitama, Japan). mPGES-1 KO mice were described previously (Kamei et al, 2004Hara et al, 2010), and were backcrossed at least 10 generations onto Balb/c mice. For experiments using LLC cells, we used mPGES-1 KO mice on a C57BL/6 background.…”

“…Immunohistochemistry of the colon tissue sections was performed as described previously (Kamei et al, 2004). Briefly, the tissue sections were incubated with Target Retrieval Solution (DAKO Japan, Kyoto, Japan) as required, incubated for 10 min with 3% (v/v) H 2 O 2 , washed three times with Trisbuffered saline (TBS) for 5 min each, incubated with 5% (w/v) skim milk for 30 min, washed three times with TBS-Tween for 5 min each and incubated for 3 h with anti-mPGES-1 antibody (Cayman Chemical, Ann Arbor, MI, USA) in TBS (1:100 dilution) or 45 min with anti-b-catenin antibody (SigmaAldrich, St Louis, MO, USA) in TBS (1:500 dilution).…”

“…Among these PGES enzymes, mPGES-1 is induced by proinflammatory stimuli and downregulated by antiinflammatory glucocorticoids, as in the case of COX-2, and is functionally coupled with COX-2 in marked preference to COX-1 (Jakobsson et al, 1999;Murakami et al, 2000;Mancini et al, 2001;Stichtenoth et al, 2001). Induction of mPGES-1 expression and its function have been observed in various diseases and systems in which COX-2-driven PGE 2 has been implicated, such as rheumatoid arthritis, febrile response, reproduction, bone metabolism, cardiovascular function, stroke and Alzheimer's disease (Kamei et al, 2004;Samuelsson et al, 2007;Hara et al, 2010). It has also been reported that mPGES-1 is constitutively expressed in several cancers, most of which also express COX-2 constitutively (Kamei et al, 2003;Golijanin et al, 2004).…”

Inhibition of Matrix Metalloproteinase-3 and -13 Synthesis Induced by IL-1β in Chondrocytes from Mice Lacking Microsomal Prostaglandin E Synthase-1

“…mPGES-1-deficient mice develop normally and do not differ from wild-type mice with respect to general appearance, behavior, and longevity (15)(16)(17)(18). In a collagen-induced arthritis model, mPGES-1-deficient mice exhibit significantly less severe and less common arthritis features compared with wild-type mice.…”

Variants of gene for microsomal prostaglandin E2 synthase show association with disease and severe inflammation in rheumatoid arthritis

“…Microsomal PGE synthase 1 (mPGES-1) is the terminal enzyme in the induced PGE 2 production at the sites of inflammation 7,8 and has an important role in the pathogenesis of inflammatory arthritis. 9,10 In humans, mPGES-1 expression is induced by proinflammatory cytokines in RA synovial fibroblasts and synovial fluid monocytes 11,12 and markedly up-regulated in RA synovial tissue. 13 In mice with experimental arthritis, genetic deletion of mPGES-1 results in significantly reduced disease incidence, severity and pain.…”