Prostaglandin‐cytokine crosstalk in chronic inflammation – ScienceOpen
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      Prostaglandin‐cytokine crosstalk in chronic inflammation

      review-article
      1 , , 2 ,
      British Journal of Pharmacology
      John Wiley and Sons Inc.

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          Abstract

          Chronic inflammation underlies various debilitating disorders including autoimmune, neurodegenerative, vascular and metabolic diseases as well as cancer, where aberrant activation of the innate and acquired immune systems is frequently seen. Since non‐steroidal anti‐inflammatory drugs exert their effects by inhibiting COX and suppressing PG biosynthesis, PGs have been traditionally thought to function mostly as mediators of acute inflammation. However, an inducible COX isoform, COX‐2, is often highly expressed in tissues of the chronic disorders, suggesting an as yet unidentified role of PGs in chronic inflammation. Recent studies have shown that in addition to their short‐lived actions in acute inflammation, PGs crosstalk with cytokines and amplify the cytokine actions on various types of inflammatory cells and drive pathogenic conversion of these cells by critically regulating their gene expression. One mode of such PG‐mediated amplification is to induce the expression of relevant cytokine receptors, which is typically observed in Th1 cell differentiation and Th17 cell expansion, events leading to chronic immune inflammation. Another mode of amplification is cooperation of PGs with cytokines at the transcription level. Typically, PGs and cytokines synergistically activate NF‐κB to induce the expression of inflammation‐related genes, one being COX‐2 itself, which makes PG‐mediated positive feedback loops. This signalling consequently enhances the expression of various NF‐κB‐induced genes including chemokines to macrophages and neutrophils, which enables sustained infiltration of these cells and further amplifies chronic inflammation. In addition, PGs are also involved in tissue remodelling such as fibrosis and angiogenesis. In this article, we review these findings and discuss their relevance to human diseases.

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          Most cited references112

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          Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis.

          Rheumatoid arthritis (RA) remains a significant unmet medical need despite significant therapeutic advances. The pathogenesis of RA is complex and includes many cell types, including T cells, B cells, and macrophages. Fibroblast-like synoviocytes (FLS) in the synovial intimal lining also play a key role by producing cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. Rheumatoid FLS develop a unique aggressive phenotype that increases invasiveness into the extracellular matrix and further exacerbates joint damage. Recent advances in understanding the biology of FLS, including their regulation regulate innate immune responses and activation of intracellular signaling mechanisms that control their behavior, provide novel insights into disease mechanisms. New agents that target FLS could potentially complement the current therapies without major deleterious effect on adaptive immune responses.
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            Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.

            Innate lymphoid cells (ILCs) are emerging as a family of effectors and regulators of innate immunity and tissue remodeling. Interleukin 22 (IL-22)- and IL-17-producing ILCs, which depend on the transcription factor RORγt, express CD127 (IL-7 receptor α-chain) and the natural killer cell marker CD161. Here we describe another lineage-negative CD127(+)CD161(+) ILC population found in humans that expressed the chemoattractant receptor CRTH2. These cells responded in vitro to IL-2 plus IL-25 and IL-33 by producing IL-13. CRTH2(+) ILCs were present in fetal and adult lung and gut. In fetal gut, these cells expressed IL-13 but not IL-17 or IL-22. There was enrichment for CRTH2(+) ILCs in nasal polyps of chronic rhinosinusitis, a typical type 2 inflammatory disease. Our data identify a unique type of human ILC that provides an innate source of T helper type 2 (T(H)2) cytokines.
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              Prostaglandin D2 Selectively Induces Chemotaxis in T Helper Type 2 Cells, Eosinophils, and Basophils via Seven-Transmembrane Receptor Crth2

              Prostaglandin (PG)D2, which has long been implicated in allergic diseases, is currently considered to elicit its biological actions through the DP receptor (DP). Involvement of DP in the formation of allergic asthma was recently demonstrated with DP-deficient mice. However, proinflammatory functions of PGD2 cannot be explained by DP alone. We show here that a seven-transmembrane receptor, CRTH2, which is preferentially expressed in T helper type 2 (Th2) cells, eosinophils, and basophils in humans, serves as the novel receptor for PGD2. In response to PGD2, CRTH2 induces intracellular Ca2+ mobilization and chemotaxis in Th2 cells in a Gαi-dependent manner. In addition, CRTH2, but not DP, mediates PGD2-dependent cell migration of blood eosinophils and basophils. Thus, PGD2 is likely involved in multiple aspects of allergic inflammation through its dual receptor systems, DP and CRTH2.
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                Author and article information

                Contributors
                chengcan.yao@ed.ac.uk
                snaru@mfour.med.kyoto-u.ac.jp
                Journal
                Br J Pharmacol
                Br. J. Pharmacol
                10.1111/(ISSN)1476-5381
                BPH
                British Journal of Pharmacology
                John Wiley and Sons Inc. (Hoboken )
                0007-1188
                1476-5381
                18 December 2018
                February 2019
                18 December 2018
                : 176
                : 3 ( doiID: 10.1111/bph.v176.3 )
                : 337-354
                Affiliations
                [ 1 ] Centre for Inflammation Research, Queen's Medical Research Institute The University of Edinburgh Edinburgh UK
                [ 2 ] Alliance Laboratory for Advanced Medical Research and Department of Drug Discovery Medicine, Medical Innovation Center Kyoto University Graduate School of Medicine Kyoto Japan
                Author notes
                [*] [* ] Correspondence

                Dr Chengcan Yao, Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK. E‐mail: chengcan.yao@ 123456ed.ac.uk ;

                Professor Shuh Narumiya, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606‐8507, Japan. E‐mail: snaru@ 123456mfour.med.kyoto-u.ac.jp

                Author information
                https://orcid.org/0000-0003-3754-2842
                Article
                BPH14530 2018-BJP-1023-RC.R1
                10.1111/bph.14530
                6329627
                30381825
                4281edc2-0b34-4bcb-8039-b07b41c7383e
                © 2018 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 18 August 2018
                : 13 October 2018
                : 17 October 2018
                Page count
                Figures: 4, Tables: 0, Pages: 18, Words: 11336
                Funding
                Funded by: Japanese Ministry for Education, Culture, Sports, Science and Technology (MEXT)
                Funded by: Ono Pharmaceuticals
                Funded by: Astellas Pharma Inc.
                Funded by: Japan Agency for Medical Research and Development
                Funded by: Cancer Research UK
                Award ID: C63480/A25246
                Funded by: Medical Research Council
                Award ID: MR/R008167/1
                Categories
                Review Article
                Review Articles
                Custom metadata
                2.0
                bph14530
                February 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.4 mode:remove_FC converted:11.01.2019

                Pharmacology & Pharmaceutical medicine
                Pharmacology & Pharmaceutical medicine

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