Transciption-independent Signaling by IL1 in Neurons

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DESCRIPTION (provided by applicant): The pro-inflammatory cytokine interleukin 1-Beta (IL-1Beta) suppresses the activity of warm sensitive neurons in the hypothalamus in vivo and in vitro, and this action appears to underlie its activity as a pyrogen (fever-inducing agent). The suppression occurs within 100-300 milliseconds after application of IL-1Beta, and the signaling mechanisms are not known. The speed of the effects suggest that NFKB mediated transcriptional changes, which are the most studied signaling pathways for IL-1Beta action, are not likely to be responsible for this rapid action of IL-1Beta. The goal of this study is to identify the molecular mechanisms of rapid IL-1Beta signaling, using thermosensitive hypothalamic neurons as a model. We will use biochemical and molecular biological, cellular, electrophysiological, and in vivo telemetrical approaches to identify the second messenger system involved in the rapid IL-1Beta effects on hypothalamic warm-sensitive neurons, and subsequently on the fever response. We have preliminary data indicating that IL-1Beta stimulation of sphingomyelinase activity through the type 1 IL-1 receptor may be involved in the rapid signaling of IL-1Beta. The cell penetrating analog of the sphingomyelinase product C2 ceramide causes rapid fever response reminiscent of the early phase of IL-1Beta induced fever. In vitro C2 ceramide activates phosphorylation of ERK in hypothalamic neurons similar to IL-1Beta. We will test the hypothesis that rapid effects of IL-1Beta involve ceramide-mediated protein phosphorylation-dependent changes in neuronal activity and that ceramide acts as second messenger of the rapid non-transcription dependent actions of IL-1Beta. Since IL-1 receptors are constitutively expressed in the hypothalamus, defining their molecular mechanisms of action will contribute to a better understanding of the neuronal effects of IL-1Beta in the hypothalamus, where it regulates the HPA axis, the temperature setpoint, and fever response