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      Ten‐year alcohol consumption typologies and trajectories of C‐reactive protein, interleukin‐6 and interleukin‐1 receptor antagonist over the following 12 years: a prospective cohort study

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          Abstract

          Background

          Moderate alcohol consumption is thought to confer cardiometabolic protective effects. Inflammatory pathways are hypothesized to partly underlie this association.

          Objectives

          The aim of this study was to examine the association between typologies of alcohol consumption and markers of inflammation, and their rate of change over time.

          Methods

          Data were collected from 8209 participants [69% men; mean age, 50 years ( SD 6.1)] of the British Whitehall II study. Alcohol consumption typologies were defined using up to three measures during an approximately 10‐year period spanning from 1985 to 1994 as (i) stable nondrinkers, (ii) stable moderate drinkers (referent), (iii) stable heavy drinkers, (iv) nonstable drinkers and (v) former drinkers. C‐reactive protein ( CRP), interleukin ( IL)‐6 and IL‐1 receptor antagonist ( IL‐1 RA) were measured up to three times in the following 12 years.

          Results

          Stable moderate drinkers had lower levels of CRP than stable nondrinkers, stable heavy drinkers, former drinkers and nonstable drinkers, but there were no differences in the rate of change in CRP over time between groups. Stable nondrinkers had higher levels of IL‐6 as did stable heavy drinkers; rates of change in IL‐6 over time were also increased in the latter group. Stable nondrinkers also had higher levels of IL‐1 RA. These associations were robust to adjustment for confounding factors.

          Conclusion

          Our novel investigation of 10‐year drinking typologies shows that stable moderate alcohol consumption is associated with a long‐term inflammatory marker profile that is consistent with conferring a reduced risk of developing coronary heart disease.

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          Most cited references73

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          Metabolic endotoxemia initiates obesity and insulin resistance.

          Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in high-fat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not whole-body, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet-induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases.
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            Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases.

            Interleukin-1 (IL-1) is a highly active pro-inflammatory cytokine that lowers pain thresholds and damages tissues. Monotherapy blocking IL-1 activity in autoinflammatory syndromes results in a rapid and sustained reduction in disease severity, including reversal of inflammation-mediated loss of sight, hearing and organ function. This approach can therefore be effective in treating common conditions such as post-infarction heart failure, and trials targeting a broad spectrum of new indications are underway. So far, three IL-1-targeted agents have been approved: the IL-1 receptor antagonist anakinra, the soluble decoy receptor rilonacept and the neutralizing monoclonal anti-IL-1β antibody canakinumab. In addition, a monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1α antibody are in clinical trials.
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              The interleukin-1 family: back to the future.

              Interleukin-1 (IL-1) is a central mediator of innate immunity and inflammation. The IL-1 family includes seven ligands with agonist activity (IL-1α and IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ), three receptor antagonists (IL-1Ra, IL-36Ra, IL-38), and an anti-inflammatory cytokine (IL-37). Members of the IL-1 Receptor (IL-1R) family include six receptor chains forming four signaling receptor complexes, two decoy receptors (IL-1R2, IL-18BP), and two negative regulators (TIR8 or SIGIRR, IL-1RAcPb). A tight regulation via receptor antagonists, decoy receptors, and signaling inhibitors ensures a balance between amplification of innate immunity and uncontrolled inflammation. All cells of the innate immune system express and/or are affected by IL-1 family members. Moreover, IL-1 family members play a key role in the differentiation and function of polarized innate and adaptive lymphoid cells. Here we will review the key properties of IL-1 family members, with emphasis on pathways of negative regulation and orchestration of innate and adaptive immunity. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                scb81@medschl.cam.ac.uk
                Journal
                J Intern Med
                J. Intern. Med
                10.1111/(ISSN)1365-2796
                JOIM
                Journal of Internal Medicine
                John Wiley and Sons Inc. (Hoboken )
                0954-6820
                1365-2796
                03 August 2016
                January 2017
                : 281
                : 1 ( doiID: 10.1111/joim.2017.281.issue-1 )
                : 75-85
                Affiliations
                [ 1 ] Research Department of Epidemiology and Public HealthUniversity College London LondonUK
                [ 2 ] UCL Institute of Liver and Digestive Health Royal Free CampusUniversity College London LondonUK
                Author notes
                [*] [* ] Correspondence: Steven Bell, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, UK.

                (fax: +44 (0)1223 748658; e‐mail: scb81@ 123456medschl.cam.ac.uk ).

                Article
                JOIM12544
                10.1111/joim.12544
                5173424
                27485145
                4a150565-f0ce-49b3-9c25-3c1ffa1b3daa
                © 2016 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

                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
                Page count
                Figures: 1, Tables: 2, Pages: 11, Words: 7914
                Funding
                Funded by: European Research Council
                Award ID: ERC‐StG‐2012‐309337_AlcoholLifecourse
                Funded by: UK Medical Research Council/Alcohol Research UK
                Award ID: MR/M006638/1
                Funded by: UK Medical Research Council
                Award ID: K013351
                Funded by: British Heart Foundation
                Award ID: RG/07/008/23674
                Funded by: Stroke Association
                Funded by: National Heart Lung and Blood Institute
                Award ID: HL036310
                Funded by: National Institute on Aging
                Award ID: AG13196
                Award ID: AG034454
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                joim12544
                January 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.0 mode:remove_FC converted:05.01.2017

                Internal medicine
                alcohol,cytokines,epidemiology,inflammation,longitudinal
                Internal medicine
                alcohol, cytokines, epidemiology, inflammation, longitudinal

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