Cytokines, such as interleukin-1 (IL-1), released from activated immune cells during sickness or injury act on the brain to stimulate the hypothalamo-pituitary-adrenal (HPA) axis. A suggested model for this effect involves paracrine actions of prostaglandin E2 (PGE2), released from local perivascular cells as a result of IL-1 binding on brainstem catecholamine neurons that project to the hypothalamus for the initiation of HPA responses. Four sets of experiments will test this model, and advance the broader goal of clarifying the circuits and mechanism underlying immune-to-brain communication. First, to evaluate a posited interaction between endothelial and perivascular cells in transducing blood-borne cytokine signals and initiating PGE2 synthesis, the sensitivity of the two cell types in expressing inducible cyclooxygenase (COX-2) and other markers of immune activation will be compared in rats and mice over a range of IL-1 and endotoxin treatments, and the cell-specific expression of potential mediators will be examined. Knockout mice will be used to assess the roles of select genes in COX-2 induction and resultant HPA responses. Transcriptional profiling of endothelial and perivascular cells isolated from immune-stimulated mice will evaluate suspected participants in this interaction and identify novel ones. Second, a liposome-mediated targeting approach will be used to selectively destroy brain macrophages, including perivascular cells. The impact of this on HPA and other acute phase endpoints, and the CNS circuitry that mediates them, will be determined using Fos-based functional anatomical assays. Third, anatomical tracing combined with PGE2 receptor localization will identify receptor mechanisms and cell groups that participate in PGE2-mediated HPA activation. Local microinjections of subtype-selective drugs will assess the involvement of specific receptors in brainstem and other implicated sites of action. Finally, because disruption of catecholamine inputs to hypothalamus only partially mitigates endotoxin-induced HPA activation, combined lesioning, tracing and Fos-based methods will be used to identify additional candidate mediators of endotoxin effects on hypothalamus, and specify the conditions under which they are called into play. Glucocorticoid mediators of the HPA axis exert potent immunosuppressive and anti-inflammatory effects. Disruption of this restraining influence on immune function has been implicated in the genesis of autoimmune disease in animal models and in man.
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