Glutamate augments retrovirus-induced immunodeficiency through chronic stimulation of the hypothalamic-pituitary- adrenal axis.
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-gamma) to Th2-dominant (IL-4, IL-10) phenotype. No significant changes in either circulating IL-1beta, IL-6, or TNF-alpha 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.
Espey
M G
MG
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA. michaele@bldg8.niddk.nih.gov
Basile
A S
AS
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D016207:Cytokines / Q000097:blood / Q000502:physiology; D016291:Dizocilpine Maleate / Q000008:administration & dosage; D018698:Glutamic Acid / Q000276:immunology / Q000502:physiology*; D007030:Hypothalamo-Hypophyseal System / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D007153:Immunologic Deficiency Syndromes / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D007260:Infusion Pumps; D009052:Leukemia Virus, Murine / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010913:Pituitary-Adrenal System / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D000276:Adjuvants, Immunologic; D016207:Cytokines; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016291:Dizocilpine Maleate