This review focuses on three key molecular mechanisms of glucocorticoid resistance in IBD: (i) decreased cytoplasmic glucocorticoid concentration secondary to increased P-glycoprotein-mediated efflux of glucocorticoid from target cells due to overexpression of the multidrug resistance gene (MDR1); (ii) impaired glucocorticoid signaling because of dysfunction at the level of the glucocorticoid receptor; and (iii) constitutive epithelial activation of proinflammatory mediators, including nuclear factor kappa B, resulting in inhibition of glucocorticoid receptor transcriptional activity.
Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux.