Glucocorticoid Receptor Mechanisms in Inflammatory Responses

Glucocorticoids are steroid hormones synthesised by the adrenal cortex that exert potent anti-inflammatory and immunomodulatory effects through the glucocorticoid receptor (GR). In the absence of ligand, GR resides in the cytoplasm bound to chaperone complexes. Hormone binding induces conformational changes, release from chaperones and translocation into the nucleus. There GR regulates target genes via transactivation—homodimer binding to glucocorticoid response elements (GREs)—and transrepression by tethering and inhibiting pro-inflammatory transcription factors such as nuclear factor κB and activator protein 1. Post-translational modifications, receptor isoforms and tissue-specific co-regulators endow versatility in GR activity, shaping cell-type-specific outcomes in macrophages, T cells and stromal cells. In innate immunity, GR suppresses cytokine production and promotes anti-inflammatory macrophage phenotypes, whereas in adaptive immunity it down-regulates T-cell proliferation and differentiation. Local regeneration of active glucocorticoids by the 11β-hydroxysteroid dehydrogenase type 1 enzyme fine-tunes inflammatory responses in tissues. Despite their efficacy, therapeutic use of glucocorticoids is limited by metabolic side effects and resistance, driving the search for selective GR modulators that dissociate beneficial anti-inflammatory actions from adverse metabolic programmes. Advances in GR structural dynamics, chromatin interactions and co-factor recruitment are illuminating pathways for resolving inflammation with reduced systemic toxicity.

Research from Nature Portfolio

Recent studies have challenged traditional views of glucocorticoid action by revealing unexpected cooperative gene induction mechanisms in inflammation control. One investigation demonstrated that glucocorticoids synergise with pro-inflammatory stimuli via p38 MAPK and MSK1 pathways to up-regulate sphingosine kinase 1 in macrophages, elevating circulating sphingosine-1-phosphate levels essential for suppressing acute lung inflammation. Inhibition of SphK1 abolishes this therapeutic effect, pinpointing a lipid mediator switch crucial to anti-inflammatory efficacy. Another study uncovered a key role for interleukin-1 receptor-associated kinase M (IRAK-M) in glucocorticoid-mediated restraint of Toll-like receptor signalling. Glucocorticoid treatment and bacterial products mutually enhance GR and NF-κB binding to the IRAK-M promoter, increasing its expression and thereby limiting pulmonary inflammation and improving survival in infection models. These findings redefine glucocorticoid control of innate immunity through induction of endogenous negative regulators.

Glucocorticoid Receptor Mechanisms in Inflammatory Responses publication trend

The graph below shows the total number of articles in glucocorticoid receptor mechanisms in inflammatory responses across all publications each year (not limited to Nature Index journals).

Technical terms

Glucocorticoid Receptor (GR): Nuclear receptor that mediates glucocorticoid signalling by binding directly to DNA or interacting with transcription factors.
Transactivation: Process by which GR homodimers bind glucocorticoid response elements to activate gene transcription.
Transrepression: Inhibition of pro-inflammatory gene expression via GR interference with factors such as NF-κB and AP-1.
Sphingosine Kinase 1 (SphK1): Enzyme generating sphingosine-1-phosphate, a lipid mediator essential for anti-inflammatory signalling.
Interleukin-1 Receptor-Associated Kinase M (IRAK-M): Endogenous inhibitor of Toll-like receptor pathways that limits excessive inflammation.
Glucocorticoid-induced Leucine Zipper (GILZ): Protein induced by glucocorticoids that suppresses inflammatory gene transcription through protein-protein interactions.

References

1. A General Introduction to Glucocorticoid Biology. Frontiers in Immunology (2019).
2. Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1. Nature Communications (2015).
3. Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M. Nature Communications (2015).
4. Tumors recycle glucocorticoids to drive Treg-mediated immunosuppression. Journal of Clinical Investigation (2023).
5. More Than Suppression: Glucocorticoid Action on Monocytes and Macrophages. Frontiers in Immunology (2019).
6. GILZ as a Mediator of the Anti-Inflammatory Effects of Glucocorticoids. Frontiers in Endocrinology (2015).