Protective Features of an Intact HPA Axis and Glucocorticoid Response

An intact HPA axis and resultant glucocorticoid responses are critical in maintaining body homeostasis and protecting against insults of a variety of sources. The importance of this has been shown in several systems but most compelling is the fact that lack of GR is incompatible with life (Cole et al., 1995). However, endogenous glucocorticoids can be removed by adrenalectomy, and adrenalectomized animals can survive provided the appropriate hormones are replaced exogenously. In addition, strain differences in glucocorticoid responsiveness are associated with differential inflammatory disease susceptibility.

Blockade of the HPA axis, either by adrenalecomy or hypophysectomy, or removal of functional GR by the antagonist RU486, has been shown to exacerbate disease course even to the extent of death in response to numerous bacterial or viral infections. Conversely, corticosterone replacement promotes survival and disease remittance. This was shown first in mice where adrenalectomy significantly reduced the lethal amount (LD50) of Escherichia coli serotype O111:B4 endotoxin (McCallum and Stith, 1982). In F334/N rats, treatment with RU486 and streptococcal cell walls (SCWs) resulted in higher mortality rates than SCW or RU486 alone (Sternberg et al., 1989a). Similarly, in LEW/N rats, myelin basic protein (MBP)-induced experimental allergic encephalomyelitis (EAE) was exacerbated by adrenalectomy. Replacement of corticosterone, depending on dose used, either returned disease status to that of control animals or completely alleviated symptoms (MacPhee et al., 1989). Furthermore, intervention of the HPA axis by hypophysectomy resulted in increased mortality rates from Salmonella (Edwards et al., 1991), and adrenalectomy increased mortality rates after murine cytomegalovirus (MCMV) virus infection, which was reversed by dexamethasone treatment (Ruzek et al., 1999).

In addition, Clostridium difficile toxin A-induced fluid secretion and inflammation, (Castagliuolo et al., 2001; Mykoniatis et al., 2003) and mortality from Shiga toxin in BALB/c mice (Gómez et al., 1998) were enhanced by RU486 and adrenalectomy. Again glucocorticoid treatment reversed these effects, increasing survival rates from Shiga toxin (Gómez et al., 1998; Palermo et al., 2000) and reversing the inflammatory responses to Clostridium difficile toxin A (Castagliuolo et al., 2001; Mykoniatis et al., 2003) in adrenalectomized animals. In fact, replacement of a physiological corticosterone dose resulted in an inflammatory response equivalent to sham-operated animals, whereas replacement of a high corticosterone dose resulted in a reduction of the inflammatory response (Castagliuolo et al., 2001).

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