Glucocorticoids exert their anti-inflammatory effects through two broad genomic mechanisms. 'Transrepression' — the primary mechanism for anti-inflammatory effects — involves:

• A Glucocorticoid receptor directly binding to GRE (glucocorticoid response element) in DNA and activating transcription of anti-inflammatory genes like lipocortin-1
• B Glucocorticoid receptor entering the nucleus and blocking RNA polymerase II binding
• C Ligand-bound glucocorticoid receptor physically interacting with and inhibiting pro-inflammatory transcription factors NF-κB and AP-1 without directly binding DNA ✓
• D Cytoplasmic glucocorticoid receptor directly sequestering inflammatory cytokines

Explanation

Glucocorticoid transrepression occurs when the ligand-activated glucocorticoid receptor (GR) physically tethers to key pro-inflammatory transcription factors — NF-κB (nuclear factor kappa B) and AP-1 (activator protein-1) — in the nucleus, preventing them from binding their cognate promoter elements. This represses transcription of cytokine genes (IL-1, IL-6, TNF-alpha, COX-2). Transrepression is distinct from transactivation (GR binding to GREs and switching on anti-inflammatory gene expression like lipocortin-1/annexin-1). Modern 'dissociated' GC design attempts to retain transrepression (anti-inflammatory) while minimizing transactivation (metabolic side effects).

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.