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Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
The mechanisms for activating the hypothalamic-pituitary-adrenal
(HPA) axis and the roles glucocorticoids play in the pathogenesis of
chronic infectious disease are largely undefined. Using the LP-BM5
model of retrovirus-induced immunodeficiency, we found alterations in
HPA axis function, manifested as an increase in circulating levels of
adrenocorticotropic hormone and corticosterone, beginning after only 3
mo of infection. These changes occurred contemporaneously with a shift
in the profile of circulating cytokines from a Th1-dominant (IFN-
)
to Th2-dominant (IL-4, IL-10) phenotype. No significant changes in
either circulating IL-1ß, IL-6, or TNF-
levels were observed in
infected mice. Administering the
N-methyl-D-aspartate receptor antagonist
MK-801 to infected mice normalized plasma adrenocorticotropic hormone
and corticosterone levels, indicating that glutamate was a major
activator of the HPA axis. Moreover, MK-801 treatment of late-stage
mice also reversed the type 1 to type 2 cytokine shift to a degree
comparable or superior to treatment with the glucocorticoid receptor
antagonist RU-486. These findings indicate that HPA axis activation
during LP-BM5 retrovirus infection is mediated by the chronic
hyperactivation of glutamatergic pathways in the hypothalamus. Through
this mechanism, the degree of peripheral immunodeficiency observed in
the late-stage disease is profoundly augmented.
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