The melanotropic neuropeptide, alpha-MSH, is known to inhibit interleukin 1 (IL1)-induced fever in the brain and systemic immune responses. The long-term objectives of this proposal, in continuation of studies underway, are to determine the mechanism of alpha-MSH modulation of IL1 action within the brain and to characterize the melanotropin receptor(s) of the brain and of lacrimal gland, a peripheral melanotropin target organ and potential tissue source for purification of brain-type melanotropin receptors. Two separate hypotheses will be tested that may explain the mechanism of action of alpha-MSH-mediated inhibition of IL1 action within the brain: A) First, that alpha-MSH inhibits IL1-induced release of prostaglandins E and/or F2- alpha, and/or interleukin-6 (IL-6), in hypothalamic cells; B) Second, that alpha-MSH inhibits IL1-induced secretion of corticotropin releasing factor (CRF), recently implicated as a mediator of fever and other IL1 actions in brain. This will be tested in vivo, by measuring febrile responses to IL1 and alpha-MSH in normal and CRF-deficient Lewis rats, and in vitro, by measuring the effects of alpha-MSH on IL1-induced CRF secretion in cultured brain cells. Based on the observed biphasic nature of alpha-MSH actions including modulation of IL1 effects, the hypothesis will also be tested that multiple melanotropin receptor forms exist in brain and in lacrimal glands, which may mediate different aspects of melanotropin-IL1 interactions: A) By determining whether different structure-function relationships exist for binding of a series of melanotropins in the septal- preoptic area, hypothalamus, midbrain and lacrimal gland; B) by determining the relationship between melanotropin receptor occupancy and stimulation of adenylate cyclase in diencephalic cells; C) by determining whether melanotropin receptors are differentially down-regulated by exposure to alpha-MSH, ACTH, or melanotropin receptor class-selective ligands; D) by determining whether melanotropin receptors exhibit differential binding kinetics or regulation by cations and guanine nucleotides; and E) by isolating and characterizing the melanotropin receptor(s) of the brain and lacrimal gland. Endogenous melanotropic neuropeptides may form part of an endogenous counterregulatory system, protecting against the damaging effects of excessive cytokine activity. By determining the mechanisms of neuropeptide-cytokine interactions and characterizing the receptors for this model class of peptides, the proposed research will advance our understanding of the coordinated response to infection and trauma, and the basis of autoimmune and inflammatory diseases.
Showing the most recent 10 out of 28 publications
