The aim of this proposal is to identify the brain-immune pathways that contribute to immunoregulation of splenic macrophage function. Based on our published evidence that ICV IL-1 modifies immune function through splenic sympathetic neurons and activation of the HPA axis, we will attempt to identify the central site of action of IL-1 and the neuroanatomical and neurochemical pathways that mediate brain effector function. We will identify the site of action of IL-1 and LPS through the activation of protein synthesis using c-fos and c-jun immunohistochemistry to identify the specific brain regions. Functional characterization will be attempted through microinjection procedures in these areas and their effects on endocrine and autonomic activity and macrophage cytokine production. Tract tracing with retrograde transport of HSV-1 virion will attempt to delineate the pathway of sympathetic innervation of the spleen. Pathways mediating the functional effects of central IL-1 and LPS will also be evaluated by stereotaxic surgical deafferentation, utilizing our experience in unilateral and bilateral cutting of efferents from the hypothalamus while sparing the hypothalamopituitary connections. Pharmacological blockade of the HPA axis and sympathetic activity will utilize anti-CRF antibodies, 6-OHDA and 5,7-DHT treatment in specific brain regions. Sympathetic control of the splenic macrophage function will be analyzed by examining LPS and MDP induction of macrophage IL-1, TGF-beta and TNF-alpha secretion and mRNA levels following nerve section. The regulation of macrophage cytokine synthesis by norepinephrine and NPY will test the hypothesis that they are potential immunosuppressive signals for control of cytokine secretion, Ia antigen expression and H202 production. A regulatory feedback loop of IL-1 from secretion by macrophages to the brain and back to suppress splenic macrophages will be tested by interrupting the hypothesized pathways through surgical sympathetectomy, adrenalectomy and surgical deafferentation. The latter will spare the HPA axis, but cut efferent fibers from the PVN to the spinal cord. These experiments will thus characterize the functional pathway which deliver regulatory signals from the brain to the splenic macrophages.
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