Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction

Abstract

Enhanced susceptibility to inflammatory and autoimmune disease can be related to impairments in HPA axis activity and associated hypocortisolism, or to glucocorticoid resistance resulting from impairments in local factors affecting glucocorticoid availability and function, including the glucocorticoid receptor (GR). The enhanced inflammation and hypercortisolism that typically characterize stress-related illnesses, such as depression, metabolic syndrome, cardiovascular disease, or osteoporosis, may also be related to increased glucocorticoid resistance. This review focuses on impaired GR function as a molecular mechanism of glucocorticoid resistance. Both genetic and environmental factors can contribute to impaired GR function. The evidence that glucocorticoid resistance can be environmentally induced has important implications for management of stress-related inflammatory illnesses and underscores the importance of prevention and management of chronic stress. The simultaneous assessment of neural, endocrine, and immune biomarkers through various noninvasive methods will also be discussed.

Figure 1

Bidirectional communication between the immune system and the HPA axis. Proinflammatory cytokines, such as TNF, IL-1, and IL-6, stimulate glucocorticoid release (cortisol in humans; corticosterone in rodents) by acting at all three levels of the HPA axis (solid blue lines). In turn, glucocorticoids negatively feedback on the immune system to suppress the further synthesis and release of proinflammatory cytokines (dashed red line). In addition, glucocorticoids regulate their own production through negative feedback on the upper levels of the HPA axis, including corticotropin-releasing hormone (CRH) in the paraventricular nucleus (PVN) of the hypothalamus and adrenocorticotropin (ACTH) in the anterior pituitary (dashed red lines). Reprinted with modifications.

Figure 2

Glucocorticoid resistance can be attributed to changes in local/cellular factors regulating glucocorticoid bioavailability and action. (1) increased corticosterone binding globulin (CBG); (2) increased expression of the multidrug resistance transporter (MDR pump); (3) decreased expression of 11β-hydroxy steroid dehydrogenase (HSD)-1 or increased expression of 11β-HSD-2; (4) reduced glucocorticoid binding to the glucocortoid receptor (GRα); (5) reduced GR translocation from the cytoplasm to the nucleus, which could be affected by its phosphorylation state (via mitogen-activated protein kinase (MAPK) pathways); (6) increased GR interaction with inflammatory-related transcription factors, such as NFκB or AP-1 (jun/fos); and 7) increased GRα interaction with GRβ. HSP = heat shock protein. Reprinted with modifications.