Neuroendocrine-Immune Interactions in Rheumatoid Arthritis: Mechanisms of Glucocorticoid Resistance

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Abstract

Rheumatoid arthritis (RA) is characterized by chronic inflammation of the synovial membrane, leading to joint destruction. Many autoimmune diseases and disease states of chronic inflammation are accompanied by alterations in the complex interactions between the endocrine, nervous and immune systems. Glucocorticoids, an end product of the hypothalamic-pituitary-adrenal axis, are a mainstay treatment for many autoimmune diseases, including RA, because of their potent anti-inflammatory action. However, about 30% of patients with RA fail to respond to steroid therapy. There are various mechanisms that may contribute to the development of glucocorticoid resistance in inflammatory disorders, which will be the subject of this review. In addition, glucocorticoid resistance may be a contributing factor in the development of inflammatory/autoimmune diseases themselves. Therefore, further elucidation of these mechanisms will reveal new targets for therapeutic intervention in the treatment of RA.

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Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens.

Esther M. Sternberg (2006)

The central nervous system (CNS) regulates innate immune responses through hormonal and neuronal routes. The neuroendocrine stress response and the sympathetic and parasympathetic nervous systems generally inhibit innate immune responses at systemic and regional levels, whereas the peripheral nervous system tends to amplify local innate immune responses. These systems work together to first activate and amplify local inflammatory responses that contain or eliminate invading pathogens, and subsequently to terminate inflammation and restore host homeostasis. Here, I review these regulatory mechanisms and discuss the evidence indicating that the CNS can be considered as integral to acute-phase inflammatory responses to pathogens as the innate immune system.

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Mechanisms of glucocorticoid receptor signaling during inflammation.

Kathleen Smoak, JOHN CIDLOWSKI (2015)

Glucocorticoids are among the most widely prescribed anti-inflammatory drugs. They act by binding to the glucocorticoid receptor (GR) that, upon activation, translocates to the nucleus and either stimulates or inhibits gene expression. GR inhibition of many proinflammatory response genes occurs through induction of the synthesis of anti-inflammatory proteins as well as through repression of proinflammatory transcription factors, such as nuclear factor-kappaB (NF-kappaB) or activator protein-1 (AP-1). In this review, we discuss the molecular mechanisms underlying GR inhibition of inflammatory responses, with an emphasis on repression of NF-kappaB and AP-1 and their respective signaling pathways.

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Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance.

J Cidlowski, J. Webster, Roxanne C. Jewell … (2001)

Inflammatory responses in many cell types are coordinately regulated by the opposing actions of NF-kappaB and the glucocorticoid receptor (GR). The human glucocorticoid receptor (hGR) gene encodes two protein isoforms: a cytoplasmic alpha form (GRalpha), which binds hormone, translocates to the nucleus, and regulates gene transcription, and a nuclear localized beta isoform (GRbeta), which does not bind known ligands and attenuates GRalpha action. We report here the identification of a tumor necrosis factor (TNF)-responsive NF-kappaB DNA binding site 5' to the hGR promoter that leads to a 1.5-fold increase in GRalpha mRNA and a 2.0-fold increase in GRbeta mRNA in HeLaS3 cells, which endogenously express both GR isoforms. However, TNF-alpha treatment disproportionately increased the steady-state levels of the GRbeta protein isoform over GRalpha, making GRbeta the predominant endogenous receptor isoform. Similar results were observed following treatment of human CEMC7 lymphoid cells with TNF-alpha or IL-1. The increase in GRbeta protein expression correlated with the development of glucocorticoid resistance.

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Journal

Journal ID (publisher-id): NIM

Journal ID (nlm-ta): Neuroimmunomodulation

Journal ID (doi): 10.1159/issn.1021-7401

Title: Neuroimmunomodulation

Publisher: S. Karger AG

ISBN: 978-3-8055-8608-5

ISBN: 978-3-8055-8609-2

ISSN (Print): 1021-7401

ISSN (Electronic): 1423-0216

Publication date Subscription-year: 2008

Publication date (Print): July 2008

Publication date (Electronic): 29 July 2008

Volume: 15

Issue: 1

Pages: 19-28

Affiliations

Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, National Institutes of Health, Rockville, Md., USA

Article

Publisher ID: 135620 Pmcid ID: PMC2920141 Other ID: Neuroimmunomodulation 2008;15:19–28

DOI: 10.1159/000135620

PMC ID: PMC2920141

PubMed ID: 18667796

SO-VID: 4d1d846a-583c-4a25-9ce3-ab6ac922c3c6

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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.

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Figures: 1, Tables: 1, References: 103, Pages: 10

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Neuroendocrine-Immune Interactions in Rheumatoid Arthritis: Mechanisms of Glucocorticoid Resistance

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Karger: Endocrinology

Most cited references 69

Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens.

Mechanisms of glucocorticoid receptor signaling during inflammation.

Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance.

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