Glucocorticoid regulation of the inflammatory response to injury

Abstract

During the first half of the 20th century, physiologists were interested in the adrenal glands primarily because adrenalectomized animals failed to survive even mild degrees of systemic stress. It eventually became clear that hormones secreted by the adrenal cortex were critical for survival and, in this context, adrenal cortical hormones were widely considered to support or stimulate important responses to stress or injury. With the purification and manufacture of adrenal cortical hormones in the 1930s and 1940s, clinicians suddenly discovered the potent anti-inflammatory actions of glucocorticoids (GCs). This dramatic, and unexpected, discovery has dominated clinical and laboratory research into GC actions throughout the second half of the 20th century. More recent research is again reporting GC-induced stimulatory effects on a variety of inflammatory response components. These effects are usually observed at low GC concentrations, close to concentrations that are observed in vivo during basal, unstimulated states. For example, GC-mediated stimulation has been reported for the hepatic acute-phase response, for cytokine secretion, expression of cytokine/chemokine receptors, and for the pro-inflammatory mediator, macrophage migration inhibition factor. It seems clear that the long-held clinical view that GCs act solely as anti-inflammatory agents needs to be re-assessed. Varying doses of GCs do not lead simply to varying degrees of inflammation suppression, but rather GCs can exert a full range of effects from permissive to stimulatory to suppressive.

Essential Role for Co-chaperone Fkbp52 but Not Fkbp51 in Androgen Receptor-mediated Signaling and Physiology

“…Because the GR knock-out mouse is a perinatal lethal (55), we expected loss of Fkbp52 or Fkbp51 to have a similar phenotype if either of these proteins exerted an essential and global effect on GR actions. A possible explanation for this lack is the stress nature of cortisol secretion in which the main function of activated GR is to attenuate overactivity by "first responder" stress pathways, such as inflammation (56,57). Thus, a defect of GR signaling in the Fkbp52-deficient animals may only be seen following a prior stress event, such as inflammatory challenge.…”

An inflammatory review of glucocorticoid actions in the CNS

“…Notably, we do not discuss the relatively extensive stimulatory effects of GCs on the acute phase response to inflammation. See (Sapolsky et al 2000;Dhabhar 2002;Yeager et al 2004) for further review of GC effects on peripheral inflammation.…”

Glucocorticoid receptor action in beneficial and side effects of steroid therapy: Lessons from conditional knockout mice

“…This finally converges on a systemic inflammatory response syndrome (SIRS). During this systemic inflammation GCs are synthesized in the adrenal gland in response to stress or systemic cytokine release following exposure to bacterial endotoxin (Yeager et al, 2004). Although treatment of septic shock with high GC doses in humans seems not to show a reduction of mortality (Meade, 2005), there are several lines of evidence that GCs indeed participate in control of this process.…”