Bacterial toxins, HIV proteins and inflammatory cytokines acting centrally induce fever, stimulate the hypothalamic-pituitary-adrenal axis (HPA), and modulate peripheral immune responses. These actions are inhibited by alpha-melanocyte stimulating hormone (alpha-MSH), a neuronal melanocortin. The long-term objectives of this proposal are to determine: whether endogenous central melanocortins modulate central neurogenic responses to infection; the factors which regulate melanocortin receptor (MCR) expression in the brain; and the central pathways involved in alpha-MSH inhibition of interleukin-1 (IL1) actions in the brain. Three hypotheses will be tested: First, that expression of MCR in brain is a physiologically regulated variable under feedback control by endogenous neuronal melanocortins and modulated by pathogens; second, that central proopiomelanocortin (POMC) neurons, through release of melanocortins, are physiological modulators of the febrile and HPA responses to infection; and third, that alpha-MSH antagonizes IL1 induction of HPA responses by acting on IL1-activated catecholaminergic neurons.
Specific aims are: l) To determine whether the expression of MCR subtypes (MC3 and MC4) in the hypothalamus and autonomic nuclei of the lower brainstem is modulated by endogenous and exogenous melanocortins, by bacterial endotoxin (LPS), and by IL1; 2) To determine whether POMC gene expression in hypothalamic and caudal medullary neurons is subject to feedback regulation by alpha-MSH, or is modulated by LPS and IL1; 3) To validate and optimize the abilities of antisense oligodeoxynucleotides (ODN) directed against mRNA encoding MC3 and MC4 to inhibit MCR subtype expression selectively in vitro, using melanoma cells deficient in native MCR and transfected with MC3 and MC4; 4) To determine whether endogenous central melanocortins modulate the febrile and HPA response to LPS, using intracerebrally administered antisense ODN directed against MC3 and MC4 mRNA in rats; 5) To determine whether central POMC neurons modulate febrile and HPA responses to LPS, using intracerebrally administered antisense ODN directed against POMC mRNA, alone and in combination with MC3- and MC4-directed antisense ODN; 6) Based on the differential distribution of MC3 and MC4 mRNA in the hypothalamus and lower brainstem, to determine whether centrally mediated alpha-MSH inhibition of IL1-induced fever, HPA activation, and peripheral immunomodulation involves the differential participation of MC3 or MC4; and 7) To determine whether alpha-MSH inhibits IL1-induced activation of HPA via influences on IL-1-activated ascending central noradrenergic fibers arising in medullary neurons. Endogenous central melanocortins may protect against the potentially destructive effects of cytokine action during infection. Pharmacological control of the activity of this system may be of therapeutic benefit in infectious and autoimmune disease.
Showing the most recent 10 out of 28 publications
