What is the mechanism of action (MOA) of corticosteroids?

Mechanism of Action of Corticosteroids

Primary Molecular Mechanism

Corticosteroids exert their therapeutic effects by binding to cytoplasmic glucocorticoid receptors (GR), which then translocate to the nucleus to either activate anti-inflammatory gene transcription or—more importantly—suppress inflammatory gene expression through interaction with pro-inflammatory transcription factors. 1

Genomic (Classical) Pathway

Receptor Activation and Nuclear Translocation

• Corticosteroids cross the cell membrane and bind to glucocorticoid receptors in the cytoplasm 2, 3
• The steroid-receptor complex undergoes activation and rapidly translocates to the nucleus 2, 4
• This process initiates changes in gene transcription that occur over 4-6 hours, explaining the delayed clinical onset 2

Gene Transactivation (Anti-inflammatory Protein Synthesis)

• Activated GR dimers bind to glucocorticoid response elements (GREs) in DNA promoter regions 2, 3
• This upregulates synthesis of anti-inflammatory proteins including:
  • Lipocortin-1 (inhibits phospholipase A2, blocking arachidonic acid release and subsequent prostaglandin/leukotriene production) 3, 5, 4
  • Interleukin-10 (anti-inflammatory cytokine) 5
  • Interleukin-1 receptor antagonist 5
  • MAPK phosphatase-1 (inhibits MAP kinase signaling pathways) 6

Gene Transrepression (Inflammatory Gene Suppression)

• This is the predominant mechanism for anti-inflammatory effects 3, 5
• GR interacts directly with pro-inflammatory transcription factors including:
  • Nuclear factor-kappa B (NF-κB) 2, 3, 6, 5
  • Activator protein-1 (AP-1) 2, 3, 6, 5
• This interaction suppresses expression of multiple inflammatory genes encoding:
  • Pro-inflammatory cytokines (TNF-α, IL-2, IL-6) 2
  • Adhesion molecules 3, 5
  • Inflammatory enzymes (COX-2) 2, 3
  • Chemokines and receptors 3, 5

Chromatin Remodeling Mechanism

Histone Deacetylation

• GR recruits histone deacetylase-2 (HDAC-2) to activated inflammatory gene complexes 2, 6
• HDAC-2 removes acetyl groups from core histones, causing DNA to coil more tightly around histones 6, 5
• This reduces accessibility of transcription factors to their DNA binding sites, thereby suppressing inflammatory gene transcription 6, 5
• This mechanism is critical—impaired HDAC-2 function (as occurs in COPD and smoking) causes corticosteroid resistance 6

Additional Metabolic and Immunologic Effects

Metabolic Actions

• Corticosteroids cause profound metabolic effects beyond anti-inflammation 1
• They modify the body's immune responses to diverse stimuli 1
• Natural glucocorticoids (hydrocortisone, cortisone) also possess salt-retaining properties 1

Anti-inflammatory Cellular Effects

• Inhibition of leukocyte migration 2
• Suppression of cytokine, prostaglandin, and leukotriene synthesis 2
• Reduction of oxidative stress through ketone body induction (in fasting states) 2
• Activation of the hypothalamic-pituitary-adrenal axis, leading to endogenous anti-inflammatory signaling 2

Critical Clinical Implications

Delayed Onset of Action

• Clinical improvement requires 4-6 hours minimum regardless of administration route 2
• This explains why corticosteroids should never replace epinephrine in acute anaphylaxis 2
• Early administration is crucial in conditions like severe alcoholic hepatitis to prevent cytokine storm progression 2

Mechanisms of Corticosteroid Resistance

• Overexpression of GR-β (dominant-negative inhibitor of glucocorticoid action) 2
• Excessive activation of NF-κB and AP-1 that "consumes" activated GR 5
• Compromised HDAC-2 function due to oxidative/nitrative stress (smoking, COPD) 6
• Increased IL-2 levels that antagonize anti-inflammatory responses 2

Tissue-Specific Considerations

• Topical corticosteroids have reduced systemic absorption, particularly loteprednol 0.5% with lower intraocular penetration 2
• Preservative-free formulations (e.g., compounded methylprednisolone 1%) are necessary for patients with severe hyperalgesia 2
• Potency classification (Classes 1-7) determines appropriate anatomic site selection 7