How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stress-response or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole.

A ligand binding domain mutation in the mouse glucocorticoid receptor functionally links chromatin remodeling and transcription initiation.

We utilized the mouse mammary tumor virus (MMTV) long terminal repeat (LTR) in vivo to understand how the interaction of the glucocorticoid receptor (GR) with a nucleosome-assembled promoter allows access of factors required for the transition from a repressed promoter to a derepressed, transcriptionally competent promoter. A mutation (C644G) in the ligand binding domain (LBD) of the mouse GR has provided information regarding the steps required in the derepression/activation process and in the functional significance of the two major transcriptional activation domains, AF1 and AF2. The mutant GR activates transcription from a transiently transfected promoter that has a disordered nucleosomal structure, though significantly less well than the wild-type GR. With an integrated, replicated promoter, which is assembled in an ordered nucleosomal array, the mutant GR does not activate transcription, and it fails to induce chromatin remodeling of the MMTV LTR promoter, as indicated by nuclease accessibility assays. Together, these findings support a two-step model for the transition of a nucleosome-assembled, repressed promoter to its transcriptionally active, derepressed form. In addition, we find that the C-terminal GR mutation is dominant over the transcription activation function of the N-terminal GR activation domain. These findings suggest that the primary activation function of the C-terminal activation domain is different from the function of the N-terminal activation domain and that it is required for derepression of the chromatin-repressed MMTV promoter.

Glucocorticoid regulation of the inflammatory response to injury.

During the first half of the 20th century, physiologists were interested in the adrenal glands primarily because adrenalectomized animals failed to survive even mild degrees of systemic stress. It eventually became clear that hormones secreted by the adrenal cortex were critical for survival and, in this context, adrenal cortical hormones were widely considered to support or stimulate important responses to stress or injury. With the purification and manufacture of adrenal cortical hormones in the 1930s and 1940s, clinicians suddenly discovered the potent anti-inflammatory actions of glucocorticoids (GCs). This dramatic, and unexpected, discovery has dominated clinical and laboratory research into GC actions throughout the second half of the 20th century. More recent research is again reporting GC-induced stimulatory effects on a variety of inflammatory response components. These effects are usually observed at low GC concentrations, close to concentrations that are observed in vivo during basal, unstimulated states. For example, GC-mediated stimulation has been reported for the hepatic acute-phase response, for cytokine secretion, expression of cytokine/chemokine receptors, and for the pro-inflammatory mediator, macrophage migration inhibition factor. It seems clear that the long-held clinical view that GCs act solely as anti-inflammatory agents needs to be re-assessed. Varying doses of GCs do not lead simply to varying degrees of inflammation suppression, but rather GCs can exert a full range of effects from permissive to stimulatory to suppressive.

Glucocorticoid receptor levels predict response to treatment in human lymphoma.

Neoplastic tumor masses from 47 adults with B cell malignant lymphomas were examined for glucocorticoid receptors and in vitro sensitivity to glucocorticoids. The patients were then treated with dexamethasone as a single agent for 5-14 days. Forty-seven percent of patients achieved at least a partial remission; 40% had no significant tumor response. Lymphoma cells from patients who responded had significantly more glucocorticoid receptor sites per cell and greater in vitro sensitivity as measured by glucocorticoid inhibition of incorporation of thymidine than did tumor cells from non-responders. Using a receptor level of 3000 sites/cell, response could accurately be predicted in 82% of patients. Our data suggest that study of tumor glucocorticoid receptors and glucocorticoid sensitivity in vitro may allow selection of those patients with lymphoma who should receive glucocorticoids as part of combination chemotherapy.

Glucocorticoids and lymphocytes. III. Effects of glucocorticoid administration on lymphocyte glucocorticoid receptors.

To determine the effects of glucocorticoid administration on the number of measured lymphocyte glucocorticoid receptor sites and the duration of such effects, seven normal volunteers were studied. Glucocorticoid receptor levels of the lymphocytes circulating in the blood of each volunteer were determined. Glucocorticoid was then administered in a regimen of a total of four doses of dexamethasone 4 mg p.o. every 6 hr. Determinations of the number of receptors were performed at 6 hr and at various subsequent times after the end of dexamethasone administration. When compared to baseline receptor numbers, six volunteers showed a decrease in receptor number after glucocorticoid administration (median maximum decrease 2,046 sites/cell). The fall in receptor number occurred rapidly, reaching a nadir within 30 hr from the end of glucocorticoid administration. The return of receptor number to baseline was more gradual, requiring from 3 to as long as 17 days in one subject. Our results suggest that in order to accurately interpret glucocorticoid receptor numbers in human lymphoid cells, glucocorticoid should not have been administered for 3 wk prior to determinations of receptor levels.