Glucocorticoid Resistance and Hypersensitivity States. Genetic and Developmental Aspects

G. P. Chrousos

Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, U.S.A.

Glucocorticoids have been used in the treatment of inflammatory and autoimmune diseases and to prevent graft rejection for over 50 years. These hormones exert their effects through cytoplasmic, heat shock protein-bound glucocorticoid receptors. Upon binding with the hormone, these receptors translocate into the nucleus where they modulate the transcription rates of responsive genes in either of two ways: by binding to specific promoter DNA sequences, the glucocorticoid-responsive elements (GRE-mediated actions), or by interacting with and altering the activity of transcription factors that regulate genes of importance to their actions (non-GRE-mediated actions). The latter include NF-κB, AP-1 and several STATs. Recently described glucocorticoid receptor coactivators and corepressors, respectively, enhance or diminish the actions of glucocorticoids on the promoter activities of glucocorticoid-responsive genes. Thus, in addition to the glucocorticoid receptor, multiple factors modulate the cell sensitivity to glucocorticoids, and may explain their gene-, cell-, tissue- and activity-dependent actions. DNA microarray analysis revealed that up to 20 percent of the human genome responds to glucocorticoids. Glucocorticoids stimulate new families of genes, such as toll-like receptors, scavengers and thrombospondins, which are involved in the early phase of the innate immune response, while their actions on the adaptive immune response are to promote humoral (Th2-directed) and to suppress cellular (Th1-directed) immunity. They do this by strongly inhibiting Th1- and by enhancing secretion of some Th2-cytokines, and by differentially regulating the signaling of these cytokines toward the same end-effect. By limiting the inflammatory reaction, glucocorticoids prevent tissue damage. Inflammatory mediators, however, decrease the responsiveness of inflamed tissues to glucocorticoids by neutralizing the glucocorticoid receptor via phosphorylation, nitrosylation, and oxidation, by sequestering important limiting coactivators, and by overwhelming it with increased quantities of activated interacting proinflammatory transcription factors, such as NF-κB.

The last decade has produced new insights into the mechanisms of glucocorticoid sensitivity and resistance among the various inflammatory, autoimmune, allergic, and infectious diseases, and into the different expression of glucocorticoid sensitivity, dependency, and resistance in patients suffering from the same disease. Both the quality and severity of the inflammatory stimulus, as well as the genetics and constitution of the patient, play key roles in defining the therapeutic efficacy and side-effects of glucocorticoids. Although glucocorticoids increase susceptibility to intracellular and opportunistic infections, they are also highly beneficial in the presence of serious systemic inflammation, when administered in a sustained fashion throughout the course of the disease. This is observed in the systemic inflammatory syndrome, acute respiratory distress syndrome (ARDS) and septic shock, and in other conditions, such as meningococcal meningitis. New studies provide support for the presence of inadequate endogenous glucocorticoid secretion, as well as of systemic inflammation-induced peripheral glucocorticoid resistance in these states. They also demonstrate that prolonged administration of moderate doses of glucocorticoids accelerates the resolution of both systemic inflammation and peripheral glucocorticoid resistance. Glucocorticoids produce side effects through their mostly GRE-mediated cardiovascular and metabolic actions, while they influence immunity primarily through non-GRE-mediated mechanisms. A better understanding of their use (administration, dose, time-course and type of glucocorticoid) might enhance their efficacy and decrease their adverse effects. Fortunately, the first generation of tissue- and immune vs. cardiovascular/metabolic effect-selective glucocorticoids is available for study and further improvement. ”Designer” glucocorticoids promise to be a great new advance in the therapy of inflammatory diseases.

Tissue-specific glucocorticoid resistance becomes clinically apparent with clinical manifestations from the hypersensitive tissue, because it is not compensated for by increased cortisol levels. This type of resistance may result in pathophysiologic processes and/or may contribute to such processes by not allowing glucocorticoids to exert their physiologic effects, e. g., antiinflammatory effects; these processes include glucocorticoid-resistant asthma, rheumatoid arthritis, osteoarthritis, Crohn’s disease and ulcerative colitis. Tissue-specific glucocorticoid resistance has also been observed in lymphoid tumor cells, which fail to respond to the lytic effects of glucocorticoids as the disease progresses. Finally, tissue-specific glucocorticoid resistance has been observed in ACTH-producing adenomatous corticotroph cells. This is characterized by impaired negative feedback regulation and, thus, uninhibited ACTH-production by pituitary adenomas (Cushing’s disease) and ectopic ACTH-secreting tumors. Tissue specific glucocorticoid hyper-sensitivity on the other hand may lead to abnormalities in systems that are hypersensitive to normal levels of glucocorticoids under physiologic conditions. The regulation of blood pressure and adipose tissue distribution represent such systems. The higher frequency of particular RFLPs of the GR or the 11β-dehydrogenase type 1 genes in patients with familial hypertension or central obesity may reflect an abnormality of the glucocorticoid transduction system in these diseases. Similarly, expression of AIDS virus proteins with GR coactivator activity, such as Vpr and Tat, may explain the insulin resistance and lipodystrophy syndrome that is seen in a large proportion of AIDS patients. Finally, a third system that might be affected by tissue-specific glucocorticoid hypersensitivity is the central nervous system. Up to 70 % of patients with chronic hypercortisolism present with depression of the atypical type, the most common cause of depression in the general population. Similarly, if the CNS targets were sensing excessive glucocorticoid effects one could expect depression as a result.