Figure 3.

Potential mechanisms for corticosteroid resistance involving the glucocorticoid receptor. Overexpression of the cytokines IL-2 plus IL-4, or IL-13, can reduce glucocorticoid receptor binding affinity and glucocorticoid receptor nuclear translocation. They act by causing phosphorylation of glucocorticoid receptor α (GRα) via the mitogen-activated protein kinase (MAPK) pathway. Phosphorylation of GRα is also mediated by c-Jun N-terminal kinase (JNK), which is stimulated by pro-inflammatory cytokines such as TNF-α. This can also inhibit glucocorticoid receptor binding to glucocorticoid response elements (GREs) and subsequent activation of anti-inflammatory gene transcription. Another potential mechanism of resistance is the excessive activation of AP-1, stimulated by TNF-α via the JNK pathway, preventing glucocorticoid receptor from binding to GREs and other transcription factors. Oxidative and nitrative stress can cause a significant reduction in histone deacetylase (HDAC)2 expression, leading to inhibited repression of inflammatory gene transcription. The impaired secretion of the anti-inflammatory cytokine IL-10 from T-regulatory (Treg) cells, and the aberrant production of IL-17 may also be responsible for the corticosteroid resistance seen in some severe asthmatics. MKP-1: MAPK phosphatase-1; GILZ: glucocorticoid-induced leucine zipper; IκBα: NF-κB inhibitor.