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Role of Endogenous Glucocorticoids in Immune System Function: Regulation and Counterregulation

Robert L. Spencer, Brian A. Kalman, Firdaus S. Dhabhar

10.1002/cphy.cp070418

Source: Supplement 23: Handbook of Physiology, The Endocrine System, Coping with the Environment: Neural and Endocrine Mechanisms

Originally published: 2001

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 In Vivo Versus in Vitro Glucocorticoids
2 Natural Versus Synthetic Glucocorticoids
2.1 Corticosteroid Receptor Subtypes
2.2 Corticosteroid‐Binding Globulin
3 Physiological Versus Nonphysiological Concentrations of Glucocorticoids
4 Factors Regulating Immune Cell Exposure to Glucocorticoids
4.1 Factors in the Absence of Immune Challenge
4.2 Factors in the Presence of Immune Challenge
5 Direct Effects of Glucocorticoids on Immune Cells
5.1 Molecular Features of Intracellular Glucocorticoid Receptors
5.2 Regulatory Effects of Glucocorticoids on the Expression of Immunologically Important Genes
5.3 Possible Alternative Mechanisms of Glucocorticoid Action
6 Strategies for Assessing the Role of Endogenous Glucocorticoids in Immune System Function
6.1 Circadian Studies
6.2 Stress Studies
6.3 In Vivo Secretagogue Stimulation Studies
6.4 Adrenalectomy and Glucocorticoid Replacement Studies
6.5 Other More Selective Manipulations of Glucocorticoid Action
7 Glucocorticoid Effects on Immune Subsystems
7.1 Immune Cell Maturation, Differentiation, and Turnover
7.2 Immune Cell Trafficking
7.3 Inflammation
7.4 Septic Shock
7.5 T helper 1 and T helper 2 Response
7.6 Antibody Production
7.7 Cytotoxicity and Delayed Type Hypersensitivity
8 General Models of Glucocorticoid Regulation of the Immune System
8.1 Counterregulatory Role of Glucocorticoids
8.2 Regulatory Role of Glucocorticoids
8.3 Regulatory Role of Glucocorticoids During Stress
8.4 Bidirectional Regulatory Effects of Glucocorticoids
Figure 1. Figure 1.

Basic relationship between the hypothalamic‐pituitary‐adrenal (HPA) axis, cortisol, and immune system. The hypothalamic, pituitary, and adrenal components of the HPA axis directly control the secretion of cortisol into the general blood circulation. Cortisol has stimulatory and inhibitory (+/‐) effects on various aspects of immune system function. Cortisol also has a direct negative feedback effect (‐) on the activity of the HPA axis. The HPA axis is stimulated (+) by central nervous system afferents responsive to circadian and stress factors. The HPA axis is also stimulated (+) either directly or indirectly by certain cytokine molecules secreted by activated immune cells.
Figure 2. Figure 2.

Levels of mineralocorticoid and glucocorticoid receptor binding in brain, pituitary, immune tissues, and peripheral blood mononuclear cells (PBMC). Tissue and cells are from rats that were adrenalectomized 24 h prior to death. No mineralocorticoid receptor binding was detected in the thymus and lymph nodes. Mineralocorticoid receptor binding was not determined in PBMC. (Data from 310.)
Figure 3. Figure 3.

Basic steps in cortisol regulation of gene transcription. Only the cortisol molecules that are not bound to corticosteroid binding globulin (CBG) are free to diffuse into a cell. The two cortisol receptor subtypes, the mineralocorticoid receptor (MR) or the glucocorticoid receptor (GR), are hormone activated transcription factors. The diagram depicts only the glucocorticoid receptor, but the basic sequence of events is believed to apply to both receptor subtypes. In the absence of hormone (unoccupied glucocorticoid receptor) the receptors are located intracellularly in the cell cytoplasm and form a heteromeric complex with other proteins (hsp90 and other accessory proteins). After cortisol binds to a hormone binding region of the receptor protein the receptor becomes activated, which results in (1) dissociation of hsp90 and other accessory proteins, (2) exposure of a DNA binding region of the receptor protein, (3) translocation of the activated receptor into the cell nucleus, (4) dimerization of two activated glucocorticoid receptors, (5) binding of the activated glucocorticoid receptor dimer to a specific sequence of DNA (glucocorticoid response element), and (6) resulting in either an increase or decrease in transcription (mRNA) of the glucocorticoid regulated target gene.
Figure 4. Figure 4.

Cyanoketone treatment (corticosterone synthesis inhibition) of rats virtually eliminates the decrease in white blood cell (WBC) and lymphocyte numbers observed during acute stress, and significantly enhances the increase in neutrophil numbers observed after the cessation of stress. Changes in WBC (A), lymphocyte (B), and neutrophil (C) numbers during 2‐h stress (restraint), and following recovery 3 h after the cessation of stress are shown (n = 5/group). The percentage of change in leukocyte numbers after 2‐h stress relative to baseline (0 h) is indicated. Statistically significant differences are indicated: *p <0.05, significantly different from 0‐h baseline (paired t test); °p <0.05, significantly different from corresponding control value (independent t test).

Reprinted with permission from [92]
Figure 5. Figure 5.

Acute stress experienced before exposure to antigen enhances a skin delayed‐type hypersensitivity (DTH) reaction to that antigen. A 6‐day time course of changes in the thickness of right pinnae of previously sensitized animals challenged with (2.4‐dinitro‐1‐fluorobenzene DNFB) (0.5% w/v) is shown. Vehicle treated control (left) pinnae showed no change in thickness during the experiment (data not shown). Data are expressed as means ± SEM (n = 6 per treatment group).

Adapted with permission from [87]


Figure 1.

Basic relationship between the hypothalamic‐pituitary‐adrenal (HPA) axis, cortisol, and immune system. The hypothalamic, pituitary, and adrenal components of the HPA axis directly control the secretion of cortisol into the general blood circulation. Cortisol has stimulatory and inhibitory (+/‐) effects on various aspects of immune system function. Cortisol also has a direct negative feedback effect (‐) on the activity of the HPA axis. The HPA axis is stimulated (+) by central nervous system afferents responsive to circadian and stress factors. The HPA axis is also stimulated (+) either directly or indirectly by certain cytokine molecules secreted by activated immune cells.



Figure 2.

Levels of mineralocorticoid and glucocorticoid receptor binding in brain, pituitary, immune tissues, and peripheral blood mononuclear cells (PBMC). Tissue and cells are from rats that were adrenalectomized 24 h prior to death. No mineralocorticoid receptor binding was detected in the thymus and lymph nodes. Mineralocorticoid receptor binding was not determined in PBMC. (Data from 310.)



Figure 3.

Basic steps in cortisol regulation of gene transcription. Only the cortisol molecules that are not bound to corticosteroid binding globulin (CBG) are free to diffuse into a cell. The two cortisol receptor subtypes, the mineralocorticoid receptor (MR) or the glucocorticoid receptor (GR), are hormone activated transcription factors. The diagram depicts only the glucocorticoid receptor, but the basic sequence of events is believed to apply to both receptor subtypes. In the absence of hormone (unoccupied glucocorticoid receptor) the receptors are located intracellularly in the cell cytoplasm and form a heteromeric complex with other proteins (hsp90 and other accessory proteins). After cortisol binds to a hormone binding region of the receptor protein the receptor becomes activated, which results in (1) dissociation of hsp90 and other accessory proteins, (2) exposure of a DNA binding region of the receptor protein, (3) translocation of the activated receptor into the cell nucleus, (4) dimerization of two activated glucocorticoid receptors, (5) binding of the activated glucocorticoid receptor dimer to a specific sequence of DNA (glucocorticoid response element), and (6) resulting in either an increase or decrease in transcription (mRNA) of the glucocorticoid regulated target gene.



Figure 4.

Cyanoketone treatment (corticosterone synthesis inhibition) of rats virtually eliminates the decrease in white blood cell (WBC) and lymphocyte numbers observed during acute stress, and significantly enhances the increase in neutrophil numbers observed after the cessation of stress. Changes in WBC (A), lymphocyte (B), and neutrophil (C) numbers during 2‐h stress (restraint), and following recovery 3 h after the cessation of stress are shown (n = 5/group). The percentage of change in leukocyte numbers after 2‐h stress relative to baseline (0 h) is indicated. Statistically significant differences are indicated: *p <0.05, significantly different from 0‐h baseline (paired t test); °p <0.05, significantly different from corresponding control value (independent t test).

Reprinted with permission from [92]


Figure 5.

Acute stress experienced before exposure to antigen enhances a skin delayed‐type hypersensitivity (DTH) reaction to that antigen. A 6‐day time course of changes in the thickness of right pinnae of previously sensitized animals challenged with (2.4‐dinitro‐1‐fluorobenzene DNFB) (0.5% w/v) is shown. Vehicle treated control (left) pinnae showed no change in thickness during the experiment (data not shown). Data are expressed as means ± SEM (n = 6 per treatment group).

Adapted with permission from [87]
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Article Title: Role of Endogenous Glucocorticoids in Immune System Function: Regulation and Counterregulation
 

How to Cite

Robert L. Spencer, Brian A. Kalman, Firdaus S. Dhabhar. Role of Endogenous Glucocorticoids in Immune System Function: Regulation and Counterregulation. Compr Physiol 2011, Supplement 23: Handbook of Physiology, The Endocrine System, Coping with the Environment: Neural and Endocrine Mechanisms: 381-423. First published in print 2001. doi: 10.1002/cphy.cp070418