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      Cytokine Dysregulation, Inflammation and Well-Being

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          Abstract

          Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis, health, and well-being. Like the stress response, the inflammatory reaction is crucial for survival and is meant to be tailored to the stimulus and time. A full-fledged systemic inflammatory reaction results in stimulation of four major programs: the acute-phase reaction, the sickness syndrome, the pain program, and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Common human diseases such as atopy/allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro- versus anti-inflammatory and T helper (Th)1versus Th2 cytokine balance. Recent evidence also indicates the involvement of pro-inflammatory cytokines in the pathogenesis of atherosclerosis and major depression, and conditions such as visceral-type obesity, metabolic syndrome and sleep disturbances. During inflammation, the activation of the stress system, through induction of a Th2 shift, protects the organism from systemic ‘overshooting’ with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones may actually facilitate inflammation through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor-α and C-reactive protein production and through activation of the corticotropin-releasing hormone/substance P-histamine axis. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the ‘systemic anti-inflammatory feedback’ and/or ‘hyperactivity’ of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression, and atherosclerosis. These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health. These hypotheses require further investigation, but the answers should provide critical insights into mechanisms underlying a variety of common human immune-related diseases.

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          Most cited references76

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          The acute phase response.

          Adult mammals respond to tissue damage by implementing the acute phase response, which comprises a series of specific physiological reactions. This review outlines the principal cellular and molecular mechanisms that control initiation of the tissue response at the site of injury, the recruitment of the systemic defense mechanisms, the acute phase response of the liver and the resolution of the acute phase response.
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            Stress and the inflammatory response: a review of neurogenic inflammation.

            The subject of neuroinflammation is reviewed. In response to psychological stress or certain physical stressors, an inflammatory process may occur by release of neuropeptides, especially Substance P (SP), or other inflammatory mediators, from sensory nerves and the activation of mast cells or other inflammatory cells. Central neuropeptides, particularly corticosteroid releasing factor (CRF), and perhaps SP as well, initiate a systemic stress response by activation of neuroendocrinological pathways such as the sympathetic nervous system, hypothalamic pituitary axis, and the renin angiotensin system, with the release of the stress hormones (i.e., catecholamines, corticosteroids, growth hormone, glucagons, and renin). These, together with cytokines induced by stress, initiate the acute phase response (APR) and the induction of acute phase proteins, essential mediators of inflammation. Central nervous system norepinephrine may also induce the APR perhaps by macrophage activation and cytokine release. The increase in lipids with stress may also be a factor in macrophage activation, as may lipopolysaccharide which, I postulate, induces cytokines from hepatic Kupffer cells, subsequent to an enhanced absorption from the gastrointestinal tract during psychologic stress. The brain may initiate or inhibit the inflammatory process. The inflammatory response is contained within the psychological stress response which evolved later. Moreover, the same neuropeptides (i.e., CRF and possibly SP as well) mediate both stress and inflammation. Cytokines evoked by either a stress or inflammatory response may utilize similar somatosensory pathways to signal the brain. Other instances whereby stress may induce inflammatory changes are reviewed. I postulate that repeated episodes of acute or chronic psychogenic stress may produce chronic inflammatory changes which may result in atherosclerosis in the arteries or chronic inflammatory changes in other organs as well.
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              Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency.

              In humans, interferon gamma (IFN-gamma) receptor deficiency leads to a predisposition to mycobacterial infections and impairs the formation of mature granulomas. Interleukin-12 (IL-12) receptor deficiency was found in otherwise healthy individuals with mycobacterial infections. Mature granulomas were seen, surrounded by T cells and centered with epithelioid and multinucleated giant cells, yet reduced IFN-gamma concentrations were found to be secreted by activated natural killer and T cells. Thus, IL-12-dependent IFN-gamma secretion in humans seems essential in the control of mycobacterial infections, despite the formation of mature granulomas due to IL-12-independent IFN-gamma secretion.
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                Author and article information

                Journal
                NIM
                Neuroimmunomodulation
                10.1159/issn.1021-7401
                Neuroimmunomodulation
                S. Karger AG
                1021-7401
                1423-0216
                2005
                September 2005
                21 September 2005
                : 12
                : 5
                : 255-269
                Affiliations
                aDivision of Rheumatology, Immunology and Allergy, Georgetown University Medical Center, Washington, D.C., bIntegrated Therapeutics Group, Inc., a subsidiary of Schering-Plough Co., Kenilworth, N.J., and cNational Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md., USA; dSan Raffaele Research Center, Rome, Italy; eUniversity of Liege, Liege, Belgium
                Article
                87104 Neuroimmunomodulation 2005;12:255–269
                10.1159/000087104
                16166805
                8470842f-a7d8-47d8-bf32-7bbae6948ed9
                © 2005 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 17 March 2005
                : 07 April 2005
                Page count
                Figures: 2, Tables: 1, References: 146, Pages: 15
                Categories
                Review

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Inflammation,Autoimmune diseases,Tumor necrosis factor,Interleukins,Stress,Cytokines

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