The long-term objective of this application is to understand how the immune and neuroendocrine systems interact when activated by stress or infection in the human and nonhuman primate.
The specific aims will focus on the inflammatory cytokines (IL-1, IL-6, TNFalpha) and mechanisms of hypothalamic-pituitary-adrenal (HPA) activation with an emphasis in the role of gonadal steroids in modulating cytokine and neuroendocrine responses. Previous studies in the investigators' laboratory have established that intracerebroventricular (icv) IL-1 stimulates the HPA axis in the monkey and that this affect can be blocked by corticotropin-releasing hormone (CRH) antagonism. Preliminary studies in the monkey indicate that icv IL-1 also causes profound suppression of lymphocyte function and marked stimulation of Il-6 secretion into peripheral blood, possibly by a CRH dependent mechanism. In this application, using rhesus monkeys, IL-1 CRH interactions in the brain and their modulation by gonadal steroids will be examined in vivo with respect to mechanisms of HPA activation and regulation of peripheral lymphocyte and cytokine responses. A major focus will be to characterize the endogenous cytokine and neuroendocrine responses caused by a physiological inflammatory challenge in the human. Low doses of a highly purified endotoxin preparation will be use to stimulate cytokine release and to characterize the HPA response in women in the presence and absence of gonadal steroids. The CNS cytokines and CRH into CSF after stimulation with endotoxin will be measured in monkeys with chronic CSF catheters, and specific cytokine antagonists will be infused icv to establish a role for the endogenous cytokines within the brain in neuroendocrine regulation. The ability of gonadal steroids to modulate central cytokine release will also be studied. These studies may relate to a wide range of human diseases since cytokine interactions in brain triggered by injury or infection may be associated with neurodegeneration and immunosuppression. If sex steroids restrain these cytokine-neuropeptide interactions, such pathology could be exacerbated when sex steroid levels fall. These studies should thus have direct relevance to the important clinical issue of sex steroid replacement during menopause and in other hypogonadal states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH055708-02
Application #
2883394
Study Section
Psychobiological, Biological, and Neurosciences Subcommittee (MHAI)
Program Officer
Winsky, Lois M
Project Start
1998-03-10
Project End
2002-02-28
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Lee, Michelle; Kim, Andrea; Conwell, Irene M et al. (2008) Effects of selective modulation of the central melanocortin-3-receptor on food intake and hypothalamic POMC expression. Peptides 29:440-7
Lee, Michelle; Kim, Andrea; Chua Jr, Streamson C et al. (2007) Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet. Am J Physiol Endocrinol Metab 293:E121-31
Lee, Michelle; Wardlaw, Sharon L (2007) The central melanocortin system and the regulation of energy balance. Front Biosci 12:3994-4010
Vulliemoz, Nicolas R; Xiao, Ennian; Xia-Zhang, Linna et al. (2006) Melanocortin modulation of inflammatory cytokine and neuroendocrine responses to endotoxin in the monkey. Endocrinology 147:1878-83
Landman, Rita E; Puder, Jardena J; Xiao, Ennian et al. (2003) Endotoxin stimulates leptin in the human and nonhuman primate. J Clin Endocrinol Metab 88:1285-91
Xiao, Ennian; Xia-Zhang, Linna; Vulliemoz, Nicolas R et al. (2003) Leptin modulates inflammatory cytokine and neuroendocrine responses to endotoxin in the primate. Endocrinology 144:4350-3
Xiao, Ennian; Xia-Zhang, Linna; Vulliemoz, Nicolas R et al. (2003) Agouti-related protein stimulates the hypothalamic-pituitary-adrenal (HPA) axis and enhances the HPA response to interleukin-1 in the primate. Endocrinology 144:1736-41
Puder, J J; Freda, P U; Goland, R S et al. (2001) Estrogen modulates the hypothalamic-pituitary-adrenal and inflammatory cytokine responses to endotoxin in women. J Clin Endocrinol Metab 86:2403-8
Wardlaw, S L (2001) Clinical review 127: Obesity as a neuroendocrine disease: lessons to be learned from proopiomelanocortin and melanocortin receptor mutations in mice and men. J Clin Endocrinol Metab 86:1442-6
Xiao, E; Xia-Zhang, L; Ferin, M et al. (2001) Differential effects of estradiol on the adrenocorticotropin responses to interleukin-6 and interleukin-1 in the monkey. Endocrinology 142:2736-41

Showing the most recent 10 out of 12 publications