Interleukin and the Magnocellular Neuroendocrine System

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DESCRIPTION (provided by applicant): Neuroendocrine systems respond to cytokines released peripherally during infection and inflammation. Emerging evidence, however, reveals that within the central nervous system there are intrinsic neural systems expressing interleukin-1beta (IL-1beta). In the magnocellular neuroendocrine system, IL-1beta is contained in secretory granules separate from oxytocin (OT) and vasopressin (VP) indicative of independent release. This cytokine may modulate secretion of neurohypophysial hormones during chronic stimulation by drinking hypertonic salt water (2 percent NaCI) and by lactation, as all three peptides become depleted from the neural lobe. The proposed research is focused on understanding the neurobiology of IL-1beta in the magnocellular system and its interaction with prostaglandins and nitric oxide (NO) in the regulation of OT release from the cell bodies and dendrites of magnocellular neurons and from their axon terminals in the neural lobe. Using immunoaffinity capillary electrophoresis with laser-induced fluorescence detection, the quantitative relation-ships among IL-1beta, OT and VP in plasma and their content in the supraoptic nucleus (SON) and neural lobe will be characterized from animals that drink 2 percent NaCI for 1, 3, 5 and 8 days and are rehydrated, as well as from rats that are lactating for 2, 5, 10, 15 and 21 days and are weaned. IL-1beta, OT and VP in the same microdialysate samples of the SON area will also be quantified by immunocapillary electrophoresis with laser-indirect fluorescence detection to examine whether a) IL-1beta infused locally alters dendritic release of OT from magnocellular neurons; b) endogenous release of IL-1beta occurs within the SON area during 1, 3, 5 or 8 days of drinking 2 percent NaCI; and c) OT and IL-1beta release in the SON area in response to drinking 2 percent NaCI is altered by an IL-1 receptor antagonist, inhibitors of prostaglandin synthesis (meclofenamate) and nitric oxide synthase (L-NAME) or by blockers of neuronal conduction (tetrodotoxin, omega conotoxin GVIA and omega-agatoxin IVA). Lastly, we will functionally map (Fos expression; immunohistochemistry) forebrain areas (subfornical organ SFO; organum vasculosum lamina terminalis, OVLT; median preoptic nucleus) that activate the magnocellular system after drinking 2 percent NaCI for 2 or 8 days and determine if intracerebroventricular administration of an IL-1 receptor antagonist alters this response. The proposed research will provide a functional assessment of IL-1beta in the magnocellular system and its neuromodulatory role on the central (intranuclear) and peripheral release of OT (and VP) from the magnocellular neuroendocrine system during chronic stimulation.