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      The role of the purinergic P2X 7 receptor in inflammation

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          Abstract

          The inflammatory process, orchestrated against a variety of injurious stimuli, is composed of three inter-related phases; initiation, propagation and resolution. Understanding the interplay between these three phases and harnessing the beneficial properties of inflammation whilst preventing its damaging effects, will undoubtedly lead to the advent of much needed therapies, particularly in chronic disease states. The P2X 7 receptor (P2X 7R) is increasingly recognised as an important cell surface regulator of several key inflammatory molecules including IL-1β, IL-18, TNF-α and IL-6. Moreover, as P2X 7R-dependent cytokine production is driven by activating the inflammasome, antagonists of this receptor are likely to have therapeutic potential as novel anti-inflammatory therapies. The function of the P2X 7R in inflammation, immunity and its potential role in disease will be reviewed and discussed.

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          Most cited references127

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          Points of control in inflammation.

          Inflammation is a complex set of interactions among soluble factors and cells that can arise in any tissue in response to traumatic, infectious, post-ischaemic, toxic or autoimmune injury. The process normally leads to recovery from infection and to healing, However, if targeted destruction and assisted repair are not properly phased, inflammation can lead to persistent tissue damage by leukocytes, lymphocytes or collagen. Inflammation may be considered in terms of its checkpoints, where binary or higher-order signals drive each commitment to escalate, go signals trigger stop signals, and molecules responsible for mediating the inflammatory response also suppress it, depending on timing and context. The non-inflammatory state does not arise passively from an absence of inflammatory stimuli; rather, maintenance of health requires the positive actions of specific gene products to suppress reactions to potentially inflammatory stimuli that do not warrant a full response.
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            A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes.

            Interleukin-1 beta (IL-1 beta)-converting enzyme cleaves the IL-1 beta precursor to mature IL-1 beta, an important mediator of inflammation. The identification of the enzyme as a unique cysteine protease and the design of potent peptide aldehyde inhibitors are described. Purification and cloning of the complementary DNA indicates that IL-1 beta-converting enzyme is composed of two nonidentical subunits that are derived from a single proenzyme, possibly by autoproteolysis. Selective inhibition of the enzyme in human blood monocytes blocks production of mature IL-1 beta, indicating that it is a potential therapeutic target.
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              Cathelicidins, multifunctional peptides of the innate immunity.

              Cathelicidins comprise a family of mammalian proteins containing a C-terminal cationic antimicrobial domain that becomes active after being freed from the N-terminal cathelin portion of the holoprotein. Many other members of this family have been identified since the first cathelicidin sequences were reported 10 years ago. The mature peptides generally show a wide spectrum of antimicrobial activity and, more recently, some of them have also been found to exert other biological activities. The human cathelicidin peptide LL-37 is chemotactic for neutrophils, monocytes, mast cells, and T cells; induces degranulation of mast cells; alters transcriptional responses in macrophages; stimulates wound vascularization and re-epithelialization of healing skin. The porcine PR-39 has also been involved in a variety of processes, including promotion of wound repair, induction of angiogenesis, neutrophils chemotaxis, and inhibition of the phagocyte NADPH oxidase activity, whereas the bovine BMAP-28 induces apoptosis in transformed cell lines and activated lymphocytes and may thus help with clearance of unwanted cells at inflammation sites. These multiple actions provide evidence for active participation of cathelicidin peptides in the regulation of the antimicrobial host defenses.
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                Author and article information

                Journal
                J Inflamm (Lond)
                Journal of Inflammation (London, England)
                BioMed Central (London )
                1476-9255
                2007
                16 March 2007
                : 4
                : 5
                Affiliations
                [1 ]MRC Centre for Inflammation Research, The Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
                [2 ]Astellas CNS Research in Edinburgh, The Chancellor's Building, The University of Edinburgh, 49 Little France Crescent, EH16 4SB, UK
                Article
                1476-9255-4-5
                10.1186/1476-9255-4-5
                1838907
                17367517
                1399e818-bb99-4c9a-bf8e-a7a9dc2c0432
                Copyright © 2007 Lister et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 December 2006
                : 16 March 2007
                Categories
                Review

                Immunology
                Immunology

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