AIDS exerts its lethal effects via immunosuppression. This project originated from the finding of a potential new mechanism by which immunosuppression occurs. We observed that, whereas interleukin-1 (IL-1) in vitro promotes immune responses, introduction of extremely small quantities of IL-1 into the ventricular system of the rat brain or stimulated release of endogenous IL-1 in brain produces rapid, profound, and long-lasting suppression of several cellular immune responses, including Natural killer (NK) cell activity, response to lymphocytes to mitogen, and interleukin-2 (IL-2) production. Subsequent studies determined that this effect requires corticotrophin releasing factor (CRF) in brain as a mediator. Other studies indicate that IL-1 in brain profoundly activates brain noradrenergic neurons, which also may be an essential link in this phenomenon. First, this proposal seeks to further characterize the immunological consequences of IL-1 in the brain by assessing effects on (a) lymphocytes in lung (b) humoral immune responses, and (c) immune changes measured in vivo. Since under physiological conditions IL-1 would likely act on brain for prolonged periods of time, these studies will examine effects of repeated (chronic) administration of IL-1 into brain as well as acute administrations. Second, we will further explore circuitry within the brain through which IL-1 affects immune response. By local infusion of IL-1 or low-dose LPS to locally stimulate IL-1, as well as local infusion of blocking agents for IL-1, NE, or CRF receptors, studies will determine how particular brain regions participate in the immunological effects of IL-1 in brain. The paraventricular nucleus of the hypothalamus, dorsal hippocampus, and central nucleus of the amygdala will be studied because these regions (a) have high concentration of IL-1, NE, and/or CRF and their receptors, (b) are sites at which IL-1, NE, and CRF affect activity (metabolism, release) of each other, and (c) are regions that importantly influence (via neural or neurohumoral routes) the two physiological systems known to mediate IL- 1 -induced effects on immune responses-the pituitary-adrenal (P-A) axis and autonomic nervous system. A new finding is that the envelope protein of human immunodeficiency virus (HIV), gpl2O, stimulates IL-1 in rat brain and consequently activates the P-A axis and suppresses cellular immune responses as does IL-1. To further explore this, effects of repeated infusion of gp120 into brain are studied. As in studies described above, gp120 will be injected into specific brain regions to determine its local actions on IL-1, NE, CRF, and immunological consequences. Also, stimulation by gpl2O of IL-1 beta mRNA in brain is examined by in situ hybridization. Finally, under physiological conditions that elevate IL-l in brain (including induction by gpl2O), IL-1 is likely to be present in conjunction with other cytokines, particularly TNFalpha and IL-6; therefore, the following questions are addressed: (a) Will TNFalpha or IL-6 produce the same immunological effects in brain as does IL-1? and (b) Do TNFalpha and IL-6 act synergistically with IL-1 in brain to increase (or possibly decrease) immunological effects of IL-1 in brain?
