The Glucocorticoid Receptor: A Revisited Target for Toxins

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis activation and glucocorticoid responses are critical for survival from a number of bacterial, viral and toxic insults, demonstrated by the fact that removal of the HPA axis or GR blockade enhances mortality rates. Replacement with synthetic glucocorticoids reverses these effects by providing protection against lethal effects. Glucocorticoid resistance/insensitivity is a common problem in the treatment of many diseases. Much research has focused on the molecular mechanism behind this resistance, but an area that has been neglected is the role of infectious agents and toxins. We have recently shown that the anthrax lethal toxin is able to repress glucocorticoid receptor function. Data suggesting that the glucocorticoid receptor may be a target for a variety of toxins is reviewed here. These studies have important implications for glucocorticoid therapy.

Systems Biology and Birth Defects Prevention: Blockade of the Glucocorticoid Receptor Prevents Arsenic-Induced Birth Defects

“…In addition, the GR pathway was also generally enriched in the genes/proteins identified for Cr, Ni, and Pb. This finding is supported by other reports that metals, including Cd, Cr, Hg, iAs, Pb, and Se, influence signaling of the GR signaling pathway (Webster Marketon and Sternberg 2010). Although these metals have been shown to be associated with the GR, the role of this pathway in mediating metal-induced developmental defects is understudied.…”

Reduced Glucocorticoid Receptor Protein Expression in Children with Critical Illness

“…Hence, many questions remain unanswered regarding relative adrenal insufficiency, CIRCI and steroid use in pediatric populations with critical illness [14,19,20]. Furthermore, since GR function may be directly targeted by bacterial toxins [39], residual GR activity may be even more limited in critical illnesses that involve infections. The analysis of GR function reported herein (i.e.…”

Microbiota Signaling Pathways that Influence Neurologic Disease

“…Glucocorticoids and the HPA axis also play a role in immunomodulation, which enhances survival from infectious diseases [50]. Depletion of HPA signaling via chemical inhibitors or adrenalectomy decreased survival in mice challenged with sublethal doses of microbial toxins, including lipopolysaccharide (LPS), shiga toxin, and Staphylococcus aureus superantignen enterotoxin B [50]. Conversely, overexpression of glucocorticoid receptor (GR) protected mice from endotoxic shock when challenged with LPS [51].…”

“…As a little-explored mechanism of virulence, microbial toxins can disrupt GR signaling. Secreted toxins from Shigella (shiga toxin), Bacillus anthracis (anthrax lethal toxin), Clostridium difficile (TcdA and TcdB), Clostridium sordellii (TscL), and S. aureus (superantigens, toxic shock syndrome toxin 1, and enterotoxin E), as well as cell wall components (endotoxin, LPS), have been shown to repress GR-mediated gene activation [50]. Whether subclinical toxin production is a mechanism by which resident microbiota regulate stress levels has not been explored.…”