Mechanism of Steroid Anti-Inflammatory Action
Steroids reduce inflammation primarily by binding to cytoplasmic glucocorticoid receptors, which translocate to the nucleus and suppress inflammatory gene transcription through histone deacetylation, while simultaneously activating anti-inflammatory gene expression. 1
Primary Molecular Pathway
Corticosteroids work through a genomic mechanism that involves several sequential steps:
Receptor binding and nuclear translocation: Steroids cross the cell membrane and bind to glucocorticoid receptors (GR) in the cytoplasm, causing the receptor to undergo activation and rapidly translocate to the nucleus 1, 2
Gene transcription suppression: The activated GR recruits histone deacetylase-2 (HDAC2) to inflammatory gene transcription complexes, which reverses histone acetylation and causes DNA to coil more tightly around histones, thereby suppressing access of pro-inflammatory transcription factors to their binding sites 3, 4
Direct transcription factor inhibition: Activated GR directly interacts with and inhibits pro-inflammatory transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), preventing them from activating inflammatory gene expression 1, 2
Specific Anti-Inflammatory Effects
The molecular actions translate into multiple anti-inflammatory effects:
Cytokine suppression: Steroids suppress expression of pro-inflammatory cytokines including TNF-α, IL-2, and IL-6 through the mechanisms described above 1
Cellular infiltration reduction: They reduce airway inflammatory cell infiltration and suppress proinflammatory mediators, cell chemotactic factors, and adhesion molecules 5
Leukocyte function inhibition: Corticosteroids inhibit leukocyte migration, suppress prostaglandin and leukotriene synthesis, and reduce oxidative stress 1
Anti-Inflammatory Gene Activation
At higher concentrations, GR homodimers also bind directly to glucocorticoid response elements (GRE) on DNA:
Increased anti-inflammatory protein production: This activates transcription of genes encoding anti-inflammatory proteins such as lipocortin-1, IL-10, IL-1 receptor antagonist, and mitogen-activated protein kinase phosphatase 2, 4
Secondary pathway contribution: While this direct gene activation contributes to anti-inflammatory effects, the primary mechanism remains the suppression of inflammatory gene transcription 2
Clinical Timing Implications
The genomic mechanism has important clinical implications:
Delayed onset of action: Clinical improvement requires a minimum of 4-6 hours regardless of administration route, because changes in gene transcription take this long to occur 1
Early administration importance: Despite the delayed onset, early administration is crucial in conditions like severe pneumonia or cytokine storm to prevent progression 6, 7
Resistance Mechanisms
Understanding the pathway also explains steroid resistance:
HDAC2 dysfunction: Oxidative and nitrative stress can markedly reduce HDAC2 activity and expression, making inflammation resistant to corticosteroids 3, 4
Transcription factor overexpression: Excessive activation of NF-κB and AP-1, overexpression of GR-β isoform, and increased IL-2 levels can all lead to corticosteroid resistance 1, 2