Neurotransmitter Regulation of Glial Cytokine Expression

描述（由申请人提供）：细胞因子白细胞介素-1（IL-1）和白细胞介素-6（IL-6）是存在于中枢神经系统中的免疫系统的促炎介质。过度的神经胶质细胞因子产生有助于神经退行性过程，例如阿尔茨海默病（AD）。IL-1激活神经胶质的机制尚不清楚，抑制性神经递质对IL-1信号传导调节的影响也是未知的。我们已经证明，IL-1刺激IL-6从C6星形细胞瘤细胞释放。抑制p38丝裂原活化蛋白激酶（MARK）会损害C6细胞中的IL-1作用，抑制性神经递质生长抑素（SRIF）和γ-氨基丁酸（GABA）也是如此。我们建议描绘一个p38驱动的途径在C6细胞和原代大鼠星形胶质细胞中的IL-1作用，并确定潜在的受体后机制，通过抑制性递质干扰IL-1驱动的信号。一个主要的假设是，p38是必不可少的IL-1刺激的IL-6从C6细胞的释放，SRIF和GABA废除通过一个或多个MAPK/SAPK途径的募集细胞内信号的阻断。我们将首先描述IL-1对p38 MARK（和SAPKs，如ERK和JNK）的激活。我们还将评估SRIF和GABA对IL-1同时激活激酶和释放IL-6的影响; IL-1信号传导下游可能的核内靶点（例如，ATF-2，c-Jun，kappaB）也将进行检查。最后，将探讨抑制性递质对反式激活因子的影响; SRIF和GABA的作用将与特定受体亚型通过具有既定受体选择性特征的类似物的潜在模仿相关。我们的研究结果应该揭示SRIF和GABA限制神经胶质细胞的炎症细胞因子的可能的细胞机制。虽然一度认为只有保护性的细胞成分在中枢神经系统中，激活星形胶质细胞和小胶质细胞提供致命的，神经毒性损伤在AD。了解神经递质可以防止这种毒性胶质细胞激活的分子机制，将为药理学废除胶质细胞介导的神经元损伤提供新的策略。

DESCRIPTION (provided by applicant): The cytokines interleukin-1 (IL-1) and'interleukin-6 (IL-6) are proinflammatory mediators of the immune system present in the central nervous system. Excessive glial cytokine production contributes to neurodegenerative processes such as Alzheimer's Disease (AD). A mechanism by which IL-1 activates glia is unknown, as are the effects of inhibitory neurotransmitters on the regulation of IL-1 signaling. We have demonstrated that IL-1 stimulates IL-6 release from C6 astrocytoma cells. Inhibition of p38 mitogen- activated protein kinase (MARK) compromises IL-1 action in C6 cells, as do the inhibitory neurotransmitters somatostatin (SRIF) and gamma-aminobutyric acid (GABA). We propose to delineate a p38-driven pathway underlying IL-1 action in C6 cells and primary rat astrocytes, and identify potential post-receptor mechanisms through which inhibitory transmitters interfere with IL-1-driven signaling. A primary hypothesis is that p38 is essential for IL-1-stimulated IL-6 release from C6 cells, and that SRIF and GABA abrogate this by blockade of intracellular signals through recruitment of one or more MAPK/SAPK pathways. We will initially describe the IL-1 activation of p38 MARK (and SAPKs such as ERK and JNK). We will also assess the influence of SRIF and GABA on concurrent kinase activation and IL-6 release by IL-1; possible ntranuclear targets downstream of IL-1 signaling (e.g., ATF-2, c-Jun, kappaB) will be examined as well. Finally, effects of inhibitory transmitters on transactivation factors will be probed; the actions of SRIF and GABA will be related to specific receptor subtypes via potential mimicry by analogs with established receptor selectivity profiles. Our results should reveal probable cellular mechanisms by which SRIF and GABA restrict glial elaboration of inflammatory cytokines. Though once considered only protective cellular elements in the CNS, activated astroctyes and microglia deliver lethal, neurotoxic insults during AD. Understanding molecular mechanisms by which neurotransmitters can prevent such toxic glial activation will provide new strategies for pharmacological abrogation of glia-mediated neuronal injury.