CYTOKINES, BEHAVIOR, AND MENTAL HEALTH

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DESCRIPTION: (Applicant's Abstract): Individuals suffering from CNS-related pathologies, such as AIDS-related dementia and Alzheimer's disease, display a variety of behavioral and neurological symptoms including memory loss, lack of motivation and deterioration of motor functions. The proinflamatory cytokines TFNa and IL-1b are expressed in the brain in response to these diseases as well as to other insults, such as stroke, trauma, and peripheral inflammation. The potent anti-inflammatory cytokines IL-4 and IL-10 have recently been localized to the CNS, and the emerging idea is that both acute and chronic inflammatory pathologies are regulated by the balance of proinflammatory and anti-inflammatory cytokines in the brain. The investigators' preliminary data showing the IL-4 and IGF-I are active in the CNS to inhibit sickness behavior induced by centrally administered LPS support this concept. Receptors for both IL-4 and IGF-I utilize a cytoplasmic docking molecule known as Insulin-Receptor Substrate-1 (IRS-1) or IRS-2 (formally known as IL-4 receptor phosphorylated substrate). The cytoplasmic docking molecules activate Phosphatidylinositol 3-Kinase (PI 3-kinase), an enzyme recently shown to be critical in protecting against cellular insults and promoting the survival of many cells, including neurons and perhaps glia. The investigators hypothesize that activation of the IRS/PI 3-kinase proteins is a common element int he signaling pathways utilized by receptors for anti-inflammatory cytokines in the CNS, and that this activations pathway is inhibited by TNFa and IL-1b. Unfortunately, the localization, expression, activation (tyrosine phosphorylation) and inhibition (serine phosphorylation) of IRS proteins in the CNS have not been identified. The investigators indicate that they now have strong preliminary data showing that both IRS-1 and IRS-2 are expressed in primary mouse glia and neurons and that IL-4, IL-10, and IGF-I activate PI 3-kinase in glial cells. The possibility that proinflammatory cytokines can directly inhibit the protective actions of anti-inflammatory cytokines in the brain would be a pivotal discovery. Indeed, IRS-recruited PI 3-kinase activity may be a critical intermediate signaling molecule in this process and is likely to provide a novel target for intervention in neuropathologies. The investigators indicate that they have developed all of the techniques and generated preliminary data to support the hypothesis of a common IRS/PI 3-kinase signaling pathways by which proinflammatory cytokines antagonize the activities of anti-inflammatory cytokine receptors in the CNS. These experiments are needed to understand the critical signaling molecules that are likely to regulate the events that lead to debilitating and costly inflammatory afflictions in the brain.