What is the mechanism of action of hydrocortisone (corticosteroid) injection?

Mechanism of Action of Hydrocortisone Injection

Hydrocortisone injection works by binding to cytoplasmic glucocorticoid receptors, which then translocate to the nucleus to modify gene transcription, resulting in potent anti-inflammatory and immunosuppressive effects through both gene activation and repression. 1

Molecular Mechanism

Receptor Binding and Nuclear Translocation

• Hydrocortisone binds to glucocorticoid receptors (GRs) in the cytoplasm of target cells 2, 3
• The steroid-receptor complex then translocates to the nucleus where it exerts its effects 3, 4
• This process modifies the body's immune responses to diverse stimuli 1

Dual Mechanism: Gene Activation (Transactivation)

Direct DNA Binding:

• Activated GRs dimerize and bind to glucocorticoid response elements (GREs) in the promoter regions of glucocorticoid-responsive genes 2, 3
• This binding increases transcription of anti-inflammatory genes 3, 4

Anti-inflammatory Proteins Induced:

• Lipocortin-1 (which inhibits phospholipase A2, blocking arachidonic acid release and subsequent prostanoid/leukotriene formation) 3, 5
• Interleukin-10 (anti-inflammatory cytokine) 3
• Interleukin-1 receptor antagonist 3, 4
• IκBα (inhibitor of NF-κB) 6

Gene Repression (Transrepression) - Primary Anti-inflammatory Effect

Transcription Factor Inhibition:

• Glucocorticoids directly inhibit pro-inflammatory transcription factors, particularly nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) 2, 3, 4
• This interaction does not require GRE binding, as most inflammatory genes lack these elements in their promoter regions 3
• This mechanism suppresses expression of multiple inflammatory genes including cytokines, enzymes, receptors, and adhesion molecules 3, 4

Chromatin Remodeling:

• Glucocorticoids interact with CREB-binding protein (CBP) and promote histone deacetylation 3
• Deacetylation causes tighter coiling of DNA around histones, reducing transcription factor access to binding sites 3
• This chromatin modification suppresses inflammatory gene expression 3, 4

Metabolic and Physiological Effects

Salt-Retaining Properties

• Naturally occurring glucocorticoids like hydrocortisone possess mineralocorticoid activity 1
• This property is important in adrenocortical deficiency states 1

Broad Metabolic Impact

• Hydrocortisone causes profound and varied metabolic effects throughout the body 1
• At high doses (300 mg), it increases glucose, insulin, and free fatty acid concentrations 6

Clinical Implications

Dose-Dependent Effects

• Low-dose hydrocortisone (10 mg/h or ~240 mg/day) attenuates systemic inflammatory response by suppressing phospholipase A2, C-reactive protein, and neutrophil elastase 7
• High-dose hydrocortisone (300 mg) paradoxically induces some pro-inflammatory effects, including increased TLR expression and HMG-B1, despite overall anti-inflammatory action 6

Time Course of Action

• Glucocorticoids require 4-6 hours for clinical improvement regardless of route, as they work through gene transcription modification 2
• This slow onset explains why they should never replace epinephrine in acute anaphylaxis 2
• However, some cellular effects (anti-inflammatory mediator upregulation, decreased mast cell mediator release) may occur within 5-30 minutes in vitro, though clinical benefit in humans is delayed 2

Important Caveats

Limitations in Acute Settings

• The mechanism of action through gene transcription means glucocorticoids are ineffective for immediate symptom relief 2
• They lack the vasoconstrictive, bronchodilatory, and ionotropic properties needed for acute emergencies 2

Potential for Resistance

• Some patients develop glucocorticoid resistance through various molecular mechanisms, including increased GR-B (a dominant negative inhibitor) or excessive IL-2 production 2
• Excessive AP-1 formation at inflammatory sites can consume activated GRs, preventing suppression of inflammatory genes 3