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.

The present study investigated the effect of alteration in thyroid hormone level on Mg(2+) homeostasis in cardiac ventricular myocytes. Hyperthyroid conditions increased cardiac myocytes total Mg(2+) content by ~14% as compared to cells from eu-thyroid animals. The excess Mg(2+) was localized predominantly within cytoplasm and mitochondria, and was mobilized into the extracellular compartment by addition of isoproterenol (ISO) or cAMP but not phenylephrine (PHE). Hypothyroid conditions, instead, decreased cardiac myocytes total Mg(2+) content by ~10% as compared to cells from eu-thyroid animals. Also in this case, cytoplasm and mitochondria were the two cellular pools predominantly affected. Under hypothyroid conditions, administration of ISO or cAMP resulted in a decreased Mg(2+) extrusion as compared to that observed in cardiac cells from eu-thyroid animals. Similar changes in cellular Mg(2+) content and transport were observed in cardiac ventricular myocytes isolated from hyper- and hypo-thyroid animals, as well as in cultures of H9C2 cells rendered hyper- or hypo-thyroid under in vitro conditions. Supplementation of thyroid hormone to hypothyroid animals restored Mg(2+) level and transport to levels comparable to those observed in eu-thyroid animals. Taken together, these results indicate that changes in thyroid hormone level have a major effect on Mg(2+) homeostasis and compartmentation in cardiac cells. The enlarged Mg(2+) mobilization via beta- but not alpha(1)-adrenergic receptor stimulation further suggests that beta- and alpha(1)-adrenergic receptors target selectively different Mg(2+) compartments within the cardiac myocyte. These results provide a new rationale to interpret changes in cardiac function under hyper- or hypo-thyroid conditions.

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