The Role of IL-1beta in Neurosecretory Function

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DESCRIPTION (provided by applicant): Our working hypothesis is that interleukin-1-beta plays a fundamental role in mediating intercellular communication in the central nervous system. Interestingly, the cellular source of IL-1-beta often determines whether its activity is beneficial or deleterious to brain function. Glial-derived IL-1-beta is predominantly associated with pathophysiological conditions, including inflammatory and neurodegenerative disorders. In contrast, neuronal IL-1-beta appears to play a critical role in modulating specific brain functions by acting as either an autocrine or paracrine signaling molecule under normal physiological conditions. However, little is known regarding the mechanisms of its actions Recent findings from this and other laboratories have demonstrated that IL-1-beta is present in the oxytocin (OT) and vasopressin (VP) neurons of the rat magnocellular neurosecretory system (MNS) where it may act to modulate neurosecretion of OT and VP by influencing neuronal-glial interactions. Our long-term objectives are to utilize the MNS as a model system for elucidating the mechanisms by which neuronal IL-1-beta modulates neuronal-glial interactions and neurosecretory activity in the CNS. The specific objectives of the proposed studies are to: 1) investigate the physiological conditions under which neuronal IL-1-beta and IL-1-beta receptor type 1 gene expression may be altered; 2) confirm and extend our preliminary observations which provided strong evidence for activity-dependent release of neuronal IL-1-beta from neurosecretory terminals. Pursuit of our objectives will be accomplished using quantitative autoradiographic in situ hybridization analysis and quantitative enzyme-linked immunoassay (ELISA) following potassium-evoked release of IL-1-beta from individual neural lobe (NL) explants maintained in culture. The R03 mechanism will allow the PI to establish the in situ hybridization histochemistry, autoradiographic and ELISA techniques critical for pursuit of these and future objectives. Fulfillment of these specific aims will increase our knowledge of the mechanisms by which cytokines affect neuronal-glial interactions and neurosecretory activity in the CNS, insights that could in turn suggest innovative approaches for cytokine therapies in neuroimmune, neuroendocrine and neurodegenerative disorders throughout the nervous system.