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      PDE4 inhibitor rolipram inhibits the expression of microsomal prostaglandin E synthase‐1 by a mechanism dependent on MAP kinase phosphatase‐1

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          Abstract

          Phosphodiesterase‐4 ( PDE4) inhibitors have recently been introduced to the treatment of COPD and psoriatic arthritis. Microsomal prostaglandin E synthase‐1 ( mPGES‐1) is an inducible enzyme synthesizing PGE 2, the most abundant prostanoid related to inflammation and inflammatory pain. mPGES‐1 is a potential drug target for novel anti‐inflammatory treatments aiming at an improved safety profile as compared to NSAIDs. Here we investigated the effect of the PDE4 inhibitor rolipram on the expression of mPGES‐1 in macrophages; and a potential mediator role in the process for MAP kinase phosphatase‐1 ( MKP‐1) which is an endogenous factor limiting the activity of the proinflammatory MAP kinases p38 and JNK. The expression of mPGES‐1 was decreased, whereas that of MKP‐1 was enhanced by rolipram in wild‐type murine macrophages. Interestingly, rolipram did not reduce mPGES‐1 expression in peritoneal macrophages from MKP‐1‐deficient mice. A reduced phosphorylation of JNK, but not p38 MAP kinase, was specifically associated with the decreased expression of mPGES‐1. Accordingly, mPGES‐1 expression was suppressed by JNK but not p38 inhibitor. These findings underline the significance of the increased MKP‐1 expression and decreased JNK phosphorylation associated with the downregulated expression of mPGES‐1 by PDE4 inhibitors in inflammation.

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          Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses.

          Engagement of Toll-like receptors (TLRs) on macrophages leads to activation of the mitogen-activated protein kinases (MAPKs), which contribute to innate immune responses. MAPK activity is regulated negatively by MAPK phosphatases (MKPs). MKP-1, the founding member of this family of dual-specificity phosphatases, has been implicated in regulating lipopolysaccharide (LPS) responses, but its role in TLR-mediated immune responses in vivo has not been defined. Here, we show that mice deficient in MKP-1 were highly susceptible to endotoxic shock in vivo, associated with enhanced production of proinflammatory cytokines TNF-alpha and IL-6 and an anti-inflammatory cytokine, IL-10. We further examined the regulation and function of MKP-1 in macrophages, a major cell type involved in endotoxic shock. MKP-1 was transiently induced by TLR stimulation through pathways mediated by both myeloid differentiation factor 88 (MyD88) and TIR domain-containing adaptor inducing IFN-beta (TRIF). MKP-1 deficiency led to sustained activation of p38 MAPK and c-Jun N-terminal kinase (JNK) in LPS-treated macrophages. In response to TLR signals, MKP-1-deficient macrophages produced 5- to 10-fold higher IL-10, which could be blocked by a p38 MAPK inhibitor. Thus, p38 MAPK plays a critical role in mediating IL-10 synthesis in TLR signaling. TNF-alpha was found to be more abundant in MKP-1-deficient macrophages within 2 hours of TLR stimulation, but its production was rapidly down-regulated by IL-10. Our studies demonstrate that MKP-1 attenuates the activities of p38 MAPK and JNK to regulate both pro- and anti-inflammatory cytokines in TLR signaling. These results highlight the complex mechanisms by which the MAPKs regulate innate immunity.
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            Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target.

            Human prostaglandin (PG) E synthase (EC 5.3.99.3) is a member of a recently recognized protein superfamily consisting of membrane associated proteins involved in eicosanoid and glutathione metabolism (the MAPEG family). Previous designations of the protein are PIG12 and MGST1-L1. PGE synthase was expressed in Escherichia coli, and both cytosolic and membrane fractions were prepared. Western blot analysis specifically detected a 15- to 16-kDa protein in the membrane fraction. Both fractions were incubated with prostaglandin H2 in the presence or absence of reduced glutathione. The membrane but not the cytosolic fraction was found to possess high glutathione-dependent PGE synthase activity (0.25 micromol/min/mg). The human tissue distribution was analyzed by Northern blot analysis. High expression of PGE synthase mRNA was detected in A549 and HeLa cancer cell lines. Intermediate level of expression was demonstrated in placenta, prostate, testis, mammary gland, and bladder whereas low mRNA expression was observed in several other tissues. A549 cells have been used as a model system to study cyclooxygenase-2 induction by IL-1beta. If A549 cells were grown in the presence of IL-1beta, a significant induction of the PGE synthase was observed by Western blot analysis. Also, Western blot analysis specifically detected a 16-kDa protein in sheep seminal vesicles. In summary, we have identified a human membrane bound PGE synthase. The enzyme activity is glutathione-dependent, and the protein expression is induced by the proinflammatory cytokine IL-1beta. PGE synthase is a potential novel target for drug development.
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              Membrane prostaglandin E synthase-1: a novel therapeutic target.

              Prostaglandin E(2) (PGE(2)) is the most abundant prostaglandin in the human body. It has a large number of biological actions that it exerts via four types of receptors, EP1-4. PGE(2) is formed from arachidonic acid by cyclooxygenase (COX-1 and COX-2)-catalyzed formation of prostaglandin H(2) (PGH(2)) and further transformation by PGE synthases. The isomerization of the endoperoxide PGH(2) to PGE(2) is catalyzed by three different PGE synthases, viz. cytosolic PGE synthase (cPGES) and two membrane-bound PGE synthases, mPGES-1 and mPGES-2. Of these isomerases, cPGES and mPGES-2 are constitutive enzymes, whereas mPGES-1 is mainly an induced isomerase. cPGES uses PGH(2) produced by COX-1 whereas mPGES-1 uses COX-2-derived endoperoxide. mPGES-2 can use both sources of PGH(2). mPGES-1 is a member of the membrane associated proteins involved in eicosanoid and glutathione metabolism (MAPEG) superfamily. It requires glutathione as an essential cofactor for its activity. mPGES-1 is up-regulated in response to various proinflammatory stimuli with a concomitant increased expression of COX-2. The coordinate increased expression of COX-2 and mPGES-1 is reversed by glucocorticoids. Differences in the kinetics of the expression of the two enzymes suggest distinct regulatory mechanisms for their expression. Studies, mainly from disruption of the mPGES-1 gene in mice, indicate key roles of mPGES-1-generated PGE(2) in female reproduction and in pathological conditions such as inflammation, pain, fever, anorexia, atherosclerosis, stroke, and tumorigenesis. These findings indicate that mPGES-1 is a potential target for the development of therapeutic agents for treatment of several diseases.
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                Author and article information

                Contributors
                eeva.moilanen@uta.fi
                Journal
                Pharmacol Res Perspect
                Pharmacol Res Perspect
                10.1002/(ISSN)2052-1707
                PRP2
                Pharmacology Research & Perspectives
                John Wiley and Sons Inc. (Hoboken )
                2052-1707
                18 October 2017
                December 2017
                : 5
                : 6 ( doiID: 10.1002/prp2.2017.5.issue-6 )
                : e00363
                Affiliations
                [ 1 ] The Immunopharmacology Research Group Faculty of Medicine and Life Sciences University of Tampere and Tampere University Hospital Tampere Finland
                Author notes
                [*] [* ] Correspondence

                Eeva Moilanen, The Immunopharmacology Research Group, Faculty of Medicine and Life Sciences, University of Tampere, FIN‐33014 Tampere, Finland. Tel: +3583 355 111; Fax: +3583 213 4473; E‐mail: eeva.moilanen@ 123456uta.fi

                Author information
                http://orcid.org/0000-0003-1284-3008
                Article
                PRP2363
                10.1002/prp2.363
                5723697
                29226622
                829f296b-dfd4-4ca8-b0e1-79aba1087652
                © 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 May 2017
                : 31 August 2017
                : 04 September 2017
                Page count
                Figures: 6, Tables: 0, Pages: 11, Words: 5681
                Funding
                Funded by: Pirkanmaa Hospital District, Finland
                Funded by: Orion Research Foundation, Finland
                Funded by: Research Foundation of Rheumatic Diseases, Finland
                Funded by: Patient Organization for Rheumatoid Arthritis (Tampereen Reumayhdistys ry), Finland
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                prp2363
                December 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.8 mode:remove_FC converted:10.12.2017

                map kinases,mkp‐1,mpges‐1,pde4
                map kinases, mkp‐1, mpges‐1, pde4

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