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Immune regulation by glucocorticoids

Key Points

  • Endogenous and pharmacological glucocorticoids exert robust effects on inflammatory and immune processes. Glucocorticoids receptors are expressed by nearly all cells in the body, yet the effects of glucocorticoids vary by cell type.

  • The production of endogenous glucocorticoids is regulated by the hypothalamic–pituitary–adrenal axis. Glucocorticoids are rapidly induced in response to inflammation and other stressors, but they also follow secretion patterns that are associated with circadian and ultradian rhythms.

  • Glucocorticoids bind cytosolic glucocorticoids receptors, which are ligand-dependent transcription factors. Ligand-bound glucocorticoid receptors regulate gene transcription through three mechanisms: direct binding to DNA via glucocorticoid response elements; protein–protein interactions with other transcription factors; and composite binding to DNA and other transcription factors.

  • Glucocorticoids inhibit inflammation by dampening signal transduction downstream of pattern recognition receptors (PRRs), cytokine receptors and Fcɛ receptors. Glucocorticoids promote the resolution of the inflammatory response through programming effects on macrophages.

  • Glucocorticoids regulate adaptive immunity by inhibiting lymphocyte activation and promoting lymphocyte apoptosis. At high concentrations, glucocorticoids also inhibit the production of B cells and T cells.

  • Glucocorticoid exposure at low doses and/or before challenge can enhance inflammatory responses. Glucocorticoid receptor signalling spares or enhances many pathways that are involved in innate immunity, while suppressing those that are involved in adaptive immunity.

  • We propose that low concentrations of endogenous glucocorticoids sensitize the innate immune system by upregulating PRRs, cytokine receptors and complement factors, thus allowing for rapid responses to danger signals. High concentrations of glucocorticoids, by contrast, suppress signals that are mediated by PRRs and cytokine receptors, thereby preventing excessive and/or prolonged immune responses.

Abstract

Endogenous glucocorticoids are crucial to various physiological processes, including metabolism, development and inflammation. Since 1948, synthetic glucocorticoids have been used to treat various immune-related disorders. The mechanisms that underlie the immunosuppressive properties of these hormones have been intensely scrutinized, and it is widely appreciated that glucocorticoids have pleiotropic effects on the immune system. However, a clear picture of the cellular and molecular basis of glucocorticoid action has remained elusive. In this Review, we distil several decades of intense (and often conflicting) research that defines the interface between the endocrine stress response and the immune system.

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Figure 1: Regulation of glucocorticoid production by the hypothalamic–pituitary–adrenal axis.
Figure 2: Mechanisms of glucocorticoid activity.
Figure 3: Effects of glucocorticoids on inflammation.
Figure 4: Glucocorticoids inhibit signalling through Toll-like receptors.
Figure 5: Glucocorticoids modulate T cell activity.
Figure 6: Glucocorticoid-induced sensitization of innate immunity.

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Acknowledgements

The authors' research of the topic of this Review was supported, in part, by the Intramural Research Program of the US National Institutes of Health, National Institute of Environmental Health Sciences.

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Correspondence to John A. Cidlowski.

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Glossary

Lympholytics

Agents that cause the death of lymphocytes.

Steroidogenesis

The enzymatic processing of cholesterol into steroid hormones.

Hypothalamic–pituitary–adrenal axis

(HPA axis). The three-organ system that receives inputs from the endocrine, neural and immune systems, and controls physiological responses to stress.

Sumoylation

A post-translational modification consisting of small ubiquitin-like modifier (SUMO) proteins.

Immunophilins

Members of a family of highly conserved cytosolic isomerases, many of which have unknown cellular functions.

Pattern recognition receptors

(PRRs). Transmembrane and cytosolic host receptors that recognize damage-associated molecular patterns and/or pathogen-associated molecular patterns.

Scavenger receptors

Members of a subclass of pattern recognition receptors that are involved in the identification and removal of unwanted molecules and cellular debris.

Positive selection

The process by which thymocytes expressing T cell receptors that bind self-peptide–MHC complexes are provided with survival signals during T cell development.

Negative selection

The process through which thymocytes expressing highly self-reactive T cell receptors are induced to undergo cell death.

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Cain, D., Cidlowski, J. Immune regulation by glucocorticoids. Nat Rev Immunol 17, 233–247 (2017). https://doi.org/10.1038/nri.2017.1

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