Glucocorticoid receptor-Nuclear factor kappa-B signaling pathway (GR-NF-κB) (GR-NF-κB)

The Glucocorticoid receptor-Nuclear factor kappa-B (GR-NF-κB) signaling pathway is a fundamental regulatory mechanism in human physiology that governs the resolution of inflammation. The Glucocorticoid Receptor (GR), a member of the nuclear receptor superfamily, remains in the cytoplasm until it binds to glucocorticoid ligands, such as cortisol or synthetic analogs like dexamethasone (UniProt: P04150). Upon activation, the GR translocates to the nucleus where it interacts with the Nuclear Factor kappa-B (NF-κB) transcription factor complex, specifically the p65 (RELA) subunit (PubMed: 21130705). This physical interaction, termed transrepression, prevents NF-κB from activating the transcription of a vast array of pro-inflammatory genes, including cytokines (IL-1, IL-6, TNF-α), chemokines, and inflammatory enzymes like COX-2 (PubMed: 15123770). This pathway is the primary target for glucocorticoid therapy, which remains the gold standard for treating chronic inflammatory conditions such as asthma, rheumatoid arthritis, and various autoimmune disorders (StatPearls: NBK538239). However, the therapeutic utility of targeting this pathway is often limited by the concurrent transactivation of other genes by the GR, which leads to significant side effects including metabolic dysfunction and bone loss. Current research focuses on developing selective glucocorticoid receptor modulators (SEGRMs) that can specifically trigger the GR-NF-κB transrepression pathway while avoiding the transactivation of genes associated with adverse effects.

Other names

NR3C1-NFKB1 interactionGlucocorticoid-mediated transrepression pathwayGR-inflammatory axisGlucocorticoid receptor-NF-kappaB complexGR-NFKB pathway

Glucocorticoid receptor ligands induce GR translocation to the nucleus where it physically tethers to NF-kappaB subunits (transrepression), inhibiting the expression of pro-inflammatory cytokines and enzymes (PubMed: 21130705).