Glucocorticoid receptor dimerization is required for proper recovery of LPS-induced inflammation, sickness behavior and metabolism in mice

M. N. Silverman; P. Mukhopadhyay; E. Belyavskaya; L. H. Tonelli; B. D. Revenis; J. H. Doran; B. E. Ballard; J. Tam; P. Pacher; E. M. Sternberg

doi:10.1038/mp.2012.131

Glucocorticoid receptor dimerization is required for proper recovery of LPS-induced inflammation, sickness behavior and metabolism in mice

M. N. Silverman, P. Mukhopadhyay, E. Belyavskaya, L. H. Tonelli, B. D. Revenis, J. H. Doran, B. E. Ballard, J. Tam, P. Pacher, E. M. Sternberg^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

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 (TNF)), enhanced early expression of brain TNF, IL-1β and IL-6 mRNA levels, and impaired later central TNF 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 TNF 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.

Original language	English
Pages (from-to)	1006-1017
Number of pages	12
Journal	Molecular Psychiatry
Volume	18
Issue number	9
DOIs	https://doi.org/10.1038/mp.2012.131
State	Published - Sep 2013
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by the NIH (intramural funds from the National Institute of Mental Health (NIMH) to EM Sternberg and from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) to P Pacher). Additional support was received by the Henry M Jackson Foundation (Bethesda, MD, USA—MNS salary) and the Center for Neuroscience and Regenerative Medicine (Uniformed Services University of the Health Sciences, Bethesda, MD, USA). We thank Dr Günther Schütz (German Cancer Research Centre, Heidelberg, Germany) for providing homozygous GRdim mouse breeder pairs to Taconic Farms (Rockville, MD, USA). We also thank Laura Tucker (Uniformed Services University of the Health Sciences, Center for Neuroscience and Regenerative Medicine, Mouse Behavioral Assessment Core, Bethesda, MD, USA) for instruction on the ANY-maze software used to analyze our open field data and Dr Sandor Batkai (Laboratory of Physiologic Studies, NIAAA, NIH, Bethesda, MD, USA) for setting up the metabolic chambers.

Keywords

HPA axis
cytokine
depression
hippocampus
hypothalamus
thermoregulation

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10.1038/mp.2012.131

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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. (2013). Glucocorticoid receptor dimerization is required for proper recovery of LPS-induced inflammation, sickness behavior and metabolism in mice. Molecular Psychiatry, 18(9), 1006-1017. https://doi.org/10.1038/mp.2012.131

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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 (TNF)), enhanced early expression of brain TNF, IL-1β and IL-6 mRNA levels, and impaired later central TNF 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 TNF 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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author = "Silverman, {M. N.} and P. Mukhopadhyay and E. Belyavskaya and Tonelli, {L. H.} and Revenis, {B. D.} and Doran, {J. H.} and Ballard, {B. E.} and J. Tam and P. Pacher and Sternberg, {E. M.}",

note = "Funding Information: This work was supported by the NIH (intramural funds from the National Institute of Mental Health (NIMH) to EM Sternberg and from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) to P Pacher). Additional support was received by the Henry M Jackson Foundation (Bethesda, MD, USA—MNS salary) and the Center for Neuroscience and Regenerative Medicine (Uniformed Services University of the Health Sciences, Bethesda, MD, USA). We thank Dr G{\"u}nther Sch{\"u}tz (German Cancer Research Centre, Heidelberg, Germany) for providing homozygous GRdim mouse breeder pairs to Taconic Farms (Rockville, MD, USA). We also thank Laura Tucker (Uniformed Services University of the Health Sciences, Center for Neuroscience and Regenerative Medicine, Mouse Behavioral Assessment Core, Bethesda, MD, USA) for instruction on the ANY-maze software used to analyze our open field data and Dr Sandor Batkai (Laboratory of Physiologic Studies, NIAAA, NIH, Bethesda, MD, USA) for setting up the metabolic chambers.",

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AU - Tonelli, L. H.

AU - Revenis, B. D.

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AU - Tam, J.

AU - Pacher, P.

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Glucocorticoid receptor dimerization is required for proper recovery of LPS-induced inflammation, sickness behavior and metabolism in mice

Abstract

Bibliographical note

Keywords

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