FIG. 4.

Mechanisms of glucocorticoid resistance. Reduction in glucocorticoid sensitivity can be ascribed to alteration of factors that regulate glucocorticoid bioavailability and activity such as [1] increased corticosteroid-binding globulin (G); [2] increased expression of the multidrug resistance transporter (MDR pump); [3] increased expression of cortisol-inactivating enzyme 11β-HSD-2; [4] reduced glucocorticoid binding to the glucocorticoid receptor (GRα); [5] inflammasome-mediated degradation of GRα; [6] reduced GR nuclear translocation due to phosphorylation by p38 and JNK classes of mitogen-activated protein kinase (MAPK); [7] increased GR interaction with inflammatory-related transcription factors, such as NF-κB or AP-1; and [8] increased expression of the inhibitory glucocorticoid receptor GRβ. HSP, heat shock protein. X indicates inhibition of gene expression. Partly adapted from Refs. 94, 105, 117, 139. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars