Glucocorticoid receptor dimerization is required for proper recovery of LPS-induced inflammation, sickness behavior and metabolism in mice
Abstract
Endogenous glucocorticoids are essential for mobilizing energy resources, restraining inflammatory responses and coordinating behavior to an immune challenge. Impaired glucocorticoid receptor (GR) function has been associated with impaired metabolic processes, enhanced inflammation and exaggerated sickness and depressive-like behaviors. To discern the molecular mechanisms underlying GR regulation of physiologic and behavioral responses to a systemic immune challenge, GR(dim) mice, in which absent GR dimerization leads to impaired GR-DNA-binding-dependent mechanisms but intact GR protein-protein interactions, were administered low-dose lipopolysaccharide (LPS). GR(dim)-LPS mice exhibited elevated and prolonged levels of plasma corticosterone (CORT), interleukin (IL)-6 and IL-10 (but not plasma tumor necrosis factor-α (TNFα)), enhanced early expression of brain TNFα, IL-1β and IL-6 mRNA levels, and impaired later central TNFα mRNA expression. Exaggerated sickness behavior (lethargy, piloerection, ptosis) in the GR(dim)-LPS mice was associated with increased early brain proinflammatory cytokine expression and late plasma CORT levels, but decreased late brain TNFα expression. GR(dim)-LPS mice also exhibited sustained locomotor impairment in the open field, body weight loss and metabolic alterations measured by indirect calorimetry, as well as impaired thermoregulation. Taken together, these data indicate that GR dimerization-dependent DNA-binding mechanisms differentially regulate systemic and central cytokine expression in a cytokine- and time-specific manner, and are essential for the proper regulation and recovery of multiple physiologic responses to low-dose endotoxin. Moreover, these results support the concept that GR protein-protein interactions are not sufficient for glucocorticoids to exert their full anti-inflammatory effects and suggest that glucocorticoid responses limited to GR monomer-mediated transcriptional effects could predispose individuals to prolonged behavioral and metabolic sequelae of an enhanced inflammatory state.
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GRdim regulatory defects are tissue-, cytokine-, and time-dependent.
“Moreover, GRdim regulatory defects were recently shown to be tissue, cytokine, and time-dependent, which further complicate the interpretation of the dimerization-dependent genomic actions of the GR (114).”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [114]
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- Authors
- Silverman, M. N., Mukhopadhyay, P., Belyavskaya, E., Tonelli, L. H., Revenis, B. D., Doran, J. H., Ballard, B. E., Tam, J., Pacher, P., & Sternberg, E. M.
- Affiliations
- National Institutes of Health (US)
- University of Maryland, Baltimore (US)
- Corresponding author
- Sternberg, E M
- Venue
- Molecular Psychiatry
- Published
- 2012-10-23
- Volume
- 18
- Issue
- 9
- Pages
- 1006-1017
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W2003936181
- Cited by
- 64
- References
- 107
- Citations by year
- 2026: 2 · 2024: 5 · 2023: 1 · 2022: 5 · 2021: 4 · 2020: 11 · 2019: 4 · 2018: 6 · 2017: 3 · 2016: 7 · 2015: 9 · 2014: 5 · 2013: 2
- FWCI
- 2.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Henry M. Jackson Foundation
- National Institutes of Health
- Uniformed Services University of the Health Sciences
- Center for Neuroscience and Regenerative Medicine
- National Institute on Alcohol Abuse and Alcoholism
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- glucocorticoid receptor, receptor dimerization, lipopolysaccharide, endotoxemia, sickness behavior, inflammation, corticosterone, cytokine expression, brain cytokines, thermoregulation, metabolic changes, locomotor impairment, weight loss, anti-inflammatory activity
- MeSH terms
- Animals, Body Temperature, Body Weight, Brain, Carbon Dioxide, Corticosterone, Gene Expression Regulation, Inflammation, Lipopolysaccharides, Male, Motor Activity, Oxygen Consumption, Receptors, Glucocorticoid, RNA, Messenger, Telemetry, Time Factors, Cytokines, Dimerization, Mice, Illness Behavior
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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