Neuron-specific effects of IL-1B

描述（由申请人提供）：炎症是脑损伤的结果，导致炎症细胞因子的产生，这有助于损伤的进展。白细胞介素-1 （IL-1）是最有效的炎症细胞因子之一，可由多种脑损伤诱导，并可增强神经元损失。IL-1抑制剂被认为是脑损伤后减轻神经元损失的治疗工具。然而，在生理条件下，IL-1也在大脑中表达，并可能在调节正常海马功能中发挥作用。我们之前已经证明，IL-1可以激活大脑中神经元和神经胶质细胞中不同的信号通路。因此，为了评估损伤后发生的炎症的后果，以及抑制炎症的潜在治疗价值，了解细胞特异性后果并区分这一关键细胞因子的生理和病理生理作用至关重要。IL-1信号通过1型IL-1受体（IL-1R1）和IL-1受体辅助蛋白（IL-1RAcP）组成的受体复合物传递。IL- 1racp的一种新的异构体，被称为AcPb，已经被发现只在中枢神经系统神经元中表达，这为研究神经元特异性IL-1作用的调控机制提供了新的机会。为了确定神经元特异性IL-1RAcPb的功能，我们将建立AcPb-/-小鼠的神经元培养物，将其与野生型神经元和缺乏这两种蛋白（AcP-/-）亚型的神经元进行比较。将分析IL-1 -¿对这些神经元的影响，以确定AcPb在介导神经元特异性信号通路中的作用，以及对神经元功能的影响。

DESCRIPTION (provided by applicant): Inflammation occurs as a consequence of brain injury, and results in the production of inflammatory cytokines, which contribute to the progression of the insult. One of the most potent inflammatory cytokines is interleukin-1 (IL-1), which is induced by many types of brain injury and can potentiate neuronal loss. IL-1 inhibitors have been suggested as therapeutic tools following brain injury to attenuate neuronal loss. However, IL-1¿ is also expressed in the brain under physiological conditions, and may play a role in mediating normal hippocampal function. We have previously demonstrated that IL-1¿ activates distinct signaling pathways in neurons versus glial cells in the brain. Therefore, to assess the consequences of inflammation that occur following injury, and the potential therapeutic value of inhibiting inflammation, it is critical to understand the cell-specific consequences and to distinguish physiological versus pathophysiologial roles for this key cytokine. IL-1 signals via a receptor complex composed of the type 1 IL-1 receptor (IL-1R1) and the IL-1 Receptor Accessory Protein (IL-1RAcP). A novel isoform of the IL-1RAcP, termed AcPb, has been identified that is expressed exclusively in CNS neurons, providing a new opportunity to investigate the mechanisms governing neuron-specific IL- 1 actions. To identify the function of the neuron-specific IL-1RAcPb we will establish neuronal cultures from AcPb-/- mice compared to wild type neurons and to neurons lacking both isoforms of the protein (AcP-/-). The effects of IL-1¿ on these neurons will be analyzed to determine the role of AcPb in mediating neuron-specific signaling pathways, and the consequences for neuronal function. PUBLIC HEALTH RELEVANCE: Interleukin-1 is a potent and pleiotropic cytokine that is induced in the brain by injury, disease, and stress. The recent identification of a neuron-specific isoform of a key IL-1 signaling protein provides a novel opportunity to investigate mechanisms governing the specific effects of IL-1 on neuronal function. These studies may also facilitate the development of therapeutic approaches to distinguish physiological versus pathophysiologial roles for this key cytokine in the brain.