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      Chemokines (CCL3, CCL4, and CCL5) Inhibit ATP-Induced Release of IL-1 β by Monocytic Cells

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          Abstract

          Chemokines and ATP are among the mediators of inflammatory sites that can enter the circulation via damaged blood vessels. The main function of chemokines is leukocyte mobilization, and ATP typically triggers inflammasome assembly. IL-1 β, a potent inflammasome-dependent cytokine of innate immunity, is essential for pathogen defense. However, excessive IL-1 β may cause life-threatening systemic inflammation. Here, we hypothesize that chemokines control ATP-dependent secretion of monocytic IL-1 β. Lipopolysaccharide-primed human monocytic U937 cells were stimulated with the P2X7 agonist BzATP for 30 min to induce IL-1 β release. CCL3, CCL4, and CCL5 dose dependently inhibited BzATP-stimulated release of IL-1 β, whereas CXCL16 was ineffective. The effect of CCL3 was confirmed for primary mononuclear leukocytes. It was blunted after silencing CCR1 or calcium-independent phospholipase A2 (iPLA2) by siRNA and was sensitive to antagonists of nicotinic acetylcholine receptors containing subunits α7 and α9. U937 cells secreted small factors in response to CCL3 that mediated the inhibition of IL-1 β release. We suggest that CCL chemokines inhibit ATP-induced release of IL-1 β from U937 cells by a triple-membrane-passing mechanism involving CCR, iPLA2, release of small mediators, and nicotinic acetylcholine receptor subunits α7 and α9. We speculate that whenever chemokines and ATP enter the circulation concomitantly, systemic release of IL-1 β is minimized.

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          Most cited references19

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          Purinergic regulation of the immune system.

          Cellular stress or apoptosis triggers the release of ATP, ADP and other nucleotides into the extracellular space. Extracellular nucleotides function as autocrine and paracrine signalling molecules by activating cell-surface P2 purinergic receptors that elicit pro-inflammatory immune responses. Over time, extracellular nucleotides are metabolized to adenosine, leading to reduced P2 signalling and increased signalling through anti-inflammatory adenosine (P1 purinergic) receptors. Here, we review how local purinergic signalling changes over time during tissue responses to injury or disease, and we discuss the potential of targeting purinergic signalling pathways for the immunotherapeutic treatment of ischaemia, organ transplantation, autoimmunity or cancer.
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            The inflammasome: an integrated view.

            An inflammasome is a multiprotein complex that serves as a platform for caspase-1 activation and caspase-1-dependent proteolytic maturation and secretion of interleukin-1β (IL-1β). Though a number of inflammasomes have been described, the NLRP3 inflammasome is the most extensively studied but also the most elusive. It is unique in that it responds to numerous physically and chemically diverse stimuli. The potent proinflammatory and pyrogenic activities of IL-1β necessitate that inflammasome activity is tightly controlled. To this end, a priming step is first required to induce the expression of both NLRP3 and proIL-1β. This event renders the cell competent for NLRP3 inflammasome activation and IL-1β secretion, and it is highly regulated by negative feedback loops. Despite the wide array of NLRP3 activators, the actual triggering of NLRP3 is controlled by integration a comparatively small number of signals that are common to nearly all activators. Minimally, these include potassium efflux, elevated levels of reactive oxygen species (ROS), and, for certain activators, lysosomal destabilization. Further investigation of how these and potentially other as yet uncharacterized signals are integrated by the NLRP3 inflammasome and the relevance of these biochemical events in vivo should provide new insight into the mechanisms of host defense and autoinflammatory conditions. © 2011 John Wiley & Sons A/S.
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              Phospholipase A2 structure/function, mechanism, and signaling.

              Tremendous advances in understanding the structure and function of the superfamily of phospholipase A2 (PLA2) enzymes has occurred in the twenty-first century. The superfamily includes 15 groups comprising four main types including the secreted sPLA2, cytosolic cPLA2, calcium-independent iPLA2, and platelet activating factor (PAF) acetyl hydrolase/oxidized lipid lipoprotein associated (Lp)PLA2. We review herein our current understanding of the structure and interaction with substrate phospholipids, which resides in membranes for a representative of each of these main types of PLA2. We will also briefly review the development of inhibitors of these enzymes and their roles in lipid signaling.
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                Author and article information

                Journal
                Mediators Inflamm
                Mediators Inflamm
                MI
                Mediators of Inflammation
                Hindawi
                0962-9351
                1466-1861
                2017
                5 July 2017
                : 2017
                : 1434872
                Affiliations
                1Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, Giessen, Germany
                2Department of Biochemistry, Faculty of Medicine, Universities of Giessen and Marburg Lung Center, Giessen, Germany
                3George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT, USA
                4Department of Biology, University of Utah, Salt Lake City, UT, USA
                5Department of Psychiatry, University of Utah, Salt Lake City, UT, USA
                6Excellence Cluster Cardiopulmonary System (ECCPS), German Center for Lung Research (DZL), Giessen, Germany
                Author notes

                Academic Editor: Paul Proost

                Author information
                http://orcid.org/0000-0001-7512-2051
                Article
                10.1155/2017/1434872
                5516742
                28757683
                c93cd439-082e-4c93-b36a-ad0c03f65663
                Copyright © 2017 Anca-Laura Amati et al.

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

                History
                : 20 January 2017
                : 31 March 2017
                : 20 April 2017
                Funding
                Funded by: National Institutes of Health
                Award ID: GM103801
                Award ID: GM48677
                Funded by: German Research Foundation
                Award ID: GR 1094/7-1
                Funded by: German Centre for Lung Research
                Categories
                Research Article

                Immunology
                Immunology

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