Figure 1.

Simplified diagrammatic representation of the mechanisms involved in an oxidant-mediated relative reduction of GC sensitivity. Oxidative stress generated by both exogenous and endogenous sources can directly (nitration and aldehyde adduct formation) and indirectly (PI3Kδ/Akt signaling) impair key transcriptional repressor proteins utilizing the GRα including HDAC-2, thus preventing GC-mediated repression of proinflammatory mediators. If the antioxidant defense response is impaired, this oxidant imbalance results in elevated inflammatory mediator expression, which GC is unable to repress.

Abbreviations: GC, glucocorticoid; PI3K, phosphoinositide 3-kinase; GR, glucocorticoid receptor; HDAC, histone deacetylase; Nrf2, NF-E2-related factor 2 (a major regulator of antioxidant gene expression).