Journal Article

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

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

2013

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/1595/1554 / 631/443/319 / 692/420/256 / 692/699/476/1414 / Adult and adolescent clinical studies / Animals / Behavior / Behavioral Sciences / Biological and medical sciences / Biological control systems / Biological Psychology / Body Temperature - drug effects / Body weight / Body Weight - drug effects / Body weight loss / Brain - drug effects / Brain - metabolism / Calorimetry / Carbon Dioxide / Cell receptors / Complications / Corticosteroids / Corticosterone / Corticosterone - blood / Cytokines / Cytokines - blood / Deoxyribonucleic acid / Depression / Depression, Mental / Dimerization / DNA / Drug dosages / Energy resources / Gene expression / Gene Expression Regulation - drug effects / Genetic aspects / Glucocorticoids / Health aspects / IL-1β / Illness Behavior - drug effects / Immune system / Inflammation / Inflammation - chemically induced / Integrative medicine / Interleukin 10 / Interleukin 6 / Lipopolysaccharides / Lipopolysaccharides - toxicity / Male / Medical sciences / Medicine / Medicine & Public Health / Mental depression / Metabolic syndrome / Metabolism / Mice / Molecular modelling / Mood disorders / Motor Activity - drug effects / Neurogenetics / Neurosciences / original-article / Oxygen Consumption - drug effects / Pharmacotherapy / Physiological aspects / Protein interaction / Proteins / Psychiatry / Psychology. Psychoanalysis. Psychiatry / Psychopathology. Psychiatry / Receptors, Glucocorticoid - metabolism / RNA, Messenger - metabolism / Sickness behavior / Telemetry / Thermoregulation / Time Factors / Transcription / Transcription factors / Tumor necrosis factor-TNF / Tumor necrosis factor-α