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.
Highlights
Bacterial and viral infections result in a cascade of events called the acute phase response resulting in inflammation, and activation of the hypothalamic-pituitary-adrenal (HPA) axis with eventual restoration of host homeostasis
In agreement with the above studies which support the role for an intact HPA axis and glucocorticoid response in survival from a toxic insult, we have shown that adrenalectomy increases lethality to anthrax lethal toxin (LeTx) in BALB/cJ, C57BL/6J and the normally LeTx resistant
Bacterial toxins can be divided into exotoxins, that are generated by the bacteria and are secreted, and endotoxins, that are a part of the bacteria itself
Summary
Bacterial and viral infections result in a cascade of events called the acute phase response resulting in inflammation, and activation of the hypothalamic-pituitary-adrenal (HPA) axis with eventual restoration of host homeostasis. Removal of endogenous glucocorticoid responses by RU486 or adrenalectomy resulted in enhanced Clostridium difficile toxin A-induced fluid secretion and inflammation [20,21] These effects of loss of HPA axis or GR function could be reversed by exogenous replacement of glucocorticoids. Increases in cytokine levels (TNFα and IL-6) following LPS/endotoxin administration are enhanced further by HPA axis blockade (adrenalectomy or RU486) and can be reversed by glucocorticoid treatment [12,24]. In agreement with the above studies which support the role for an intact HPA axis and glucocorticoid response in survival from a toxic insult, we have shown that adrenalectomy increases lethality to anthrax lethal toxin (LeTx) in BALB/cJ, C57BL/6J and the normally LeTx resistant. It has long been known that bacterial endotoxin or LPS affects GR function
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