ALCOHOL AND BRAIN INTERLEUKIN 1

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APPLICANT S ABSTRACT: Alcohol (ethanol-ETOH) abuse produces pathological effects including various brain dysfunction and immune impairment associated with increased susceptibility to various infections. One central abnormality is EtOH activation of the hypothalamic-pituitary-adrenal (HPA) axis. Although stimulation of hypothalamic corticotropin-releasing hormone (CRH) producing neurons is critical for EtOH-induced HPA activation, a precise understanding of how this occurs remains to be established. Of potential relevance, interleukin (IL)-l potently stimulates the HPA axis, is produced in hypothalamus, and stimulates common cellular signals as EtOH. Preliminary results in our laboratory show that EtOH increases IL-1beta mRNA in primary hypothalamic neuronal and glial cultures. Thus, EtOH could activate the HPA axis by increasing hypothalamic IL-1 signaling. The proposed hypothesis is that EtOH induces hypothalamic IL-1, in vitro and in vivo studies will demonstrate: 1) effects of acute and chronic EtOH on expression of IL-1beta mRNA(RNase protection assay) and IL-1beta (immunocytochemistry-ICC) and on immune/cytokine stimulation in fetal rat hypothalamic neuronal, astrocytic and microglial cultures, and 2) effects of an EtOH diet on adult rat hypothalamic IL-1beta mRNA and IL-1beta and HPA axis activation. HPA axis activation occurs in alcoholics and can cause peripheral immunosuppression via glucocorticoid-dependent and -independent mechanisms. Recognizing that central effects of IL-1 can also cause peripheral immunosuppression via both these pathways, EtOH induction of brain IL-1 could lead to immunosuppression via these central mechanisms. The well recognized impaired immunity in alcoholics could be further attenuated by mechanisms involving central cytokine dysfunction which could contribute to the high prevalence of HIV infection in alcoholics and progression to AIDS. Long term goals are to learn about mechanisms mediating EtOH effects on the brain IL-1 system and to determine the role and significance of these alterations relative to EtOH-induced HPA axis activation and peripheral immunosuppression.