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      Activation of the Hypothalamic- Pituitary-Adrenal Axis in IL-1β-Converting Enzyme-Deficient Mice

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          Abstract

          Interleukin-1β (IL-1β) plays a key role in immune, behavioral and neuroendocrine responses to inflammation or infection. IL-1β could also be involved in the response of the hypothalamic-pituitary-adrenal (HPA) axis during stress. Mature IL-1β derives from a 31-kD precursor (pro-IL-1β) that is processed by IL-1β-converting enzyme (ICE). Mice in which the ICE gene has been nullated by homologous recombination were used to investigate the role of IL-1β in the HPA axis response. Plasma levels of corticosterone and adrenocorticotropic hormone (ACTH) in response to an intraperitoneal injection of 5 μg lipopolysaccharide (LPS) were similar in ICE-deficient mice and wild-type (WT) controls. In contrast, plasma ACTH response to restraint or to 200 ng of rat recombinant IL-1β (rrIL-1β) was higher in ICE-deficient mice as compared to WT animals. This hyperreactivity of the HPA axis in ICE knockout mice appears not to be related to the production of plasma IL-1β or IL-6, which was similar to that of WT mice after rrIL-1β injection. After lypopolysaccharide, ICE-deficient mice exhibited a smaller increase in plasma-immunoreactive IL-1β and IL-6 as compared to WT controls. After restraint stress neither increase in plasma IL-1β nor IL-6 was observed. The mechanisms responsible for the increased reactivity of the HPA axis in ICE-deficient mice may result from a higher sensitivity of the HPA axis to inflammatory cytokines or to cleavage products of pro-IL-1β processed by non-ICE proteases.

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          Most cited references 7

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          Regulation of the HPA axis by cytokines.

          Cytokines are a group of polypeptide mediators, classically associated with the regulation of immunity and inflammation. However, these peptides regulate not only local immune/inflammatory responses, but also elicit many CNS-mediated responses which accompany such immune/inflammatory reactions. This article reviews the evidence that interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNFalpha) produce hypothalamo-pituitary-adrenal (HPA) axis activation in response to various threats to homeostasis. To aid such an examination, and to gain insights into the potential mechanisms by which these cytokines influence the HPA axis, experimental findings are discussed within a framework of criteria. If a particular cytokine plays a significant role in the regulation of the HPA axis in response to a particular pathophysiology, then necessarily: (1) receptors for that cytokine should be present within tissues associated with the HPA axis; (2) administration of that cytokine should elicit HPA activation; (3) the HPA axis should be exposed to that cytokine; and (4) inhibition of the action of that cytokine should prevent HPA activation. The evidence discussed indicates that some, if not all, of these criteria are met for each of IL-1, IL-6, and TNFalpha. However, the extensive interactions between different cytokines, the broad spectrum of pathophysiologies associated with increased cytokine production (including inflammatory and non-inflammatory stresses), and the number of tissues/cells capable of either synthesizing or responding to cytokines, suggest that multiple mechanisms mediate the influence of cytokines on the HPA axis.
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            Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice

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              Immobilization stress induces interleukin-1β mRNA in the rat hypothalamus

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                Author and article information

                Journal
                NIM
                Neuroimmunomodulation
                10.1159/issn.1021-7401
                Neuroimmunomodulation
                S. Karger AG
                1021-7401
                1423-0216
                2000
                May 2000
                04 May 2000
                : 7
                : 4
                : 189-194
                Affiliations
                aINSERM U.394 Neurobiologie Intégrative, Institut François-Magendie, Bordeaux, France; bLaboratory of Immunophysiology, University of Illinois, Urbana, Ill., USA
                Article
                26438 Neuroimmunomodulation 2000;7:189–194
                10.1159/000026438
                10810251
                © 2000 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.

                Page count
                Figures: 3, References: 29, Pages: 6
                Categories
                Original Paper

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