Neurotransmitter Regulation of Glial Cytokine Expression

描述(申请人提供)：细胞因子白介素1(IL-1)和白介素6(IL-6)是存在于中枢神经系统的免疫系统的促炎介质。神经胶质细胞因子的过度产生会导致神经退行性变，如阿尔茨海默病(AD)。IL-1激活胶质细胞的机制尚不清楚，抑制性神经递质对IL-1信号调节的影响也是未知的。我们已经证明了IL-1刺激C6星形细胞瘤细胞释放IL-6。抑制p38丝裂原活化蛋白激酶(MARK)会影响IL-1在C6细胞中的作用，抑制神经递质生长抑素(SRIF)和γ-氨基丁酸(GABA)也是如此。我们建议在C6细胞和原代大鼠星形胶质细胞中描绘p38驱动的IL-1作用途径，并确定潜在的受体后机制，通过抑制递质干扰IL-1驱动的信号转导。一个基本的假设是，p38是IL-1刺激的C6细胞释放IL-6所必需的，SRIF和GABA通过招募一个或多个MAPK/SAPK通路来阻断细胞内信号，从而消除这一点。我们将首先描述p38Mark(以及SAPKs，如ERK和JNK)对IL-1的激活。我们还将评估SRIF和GABA对IL-1同时激活的激酶和释放IL-6的影响；也将检测IL-1信号下游的可能核内靶点(例如，ATF-2、c-Jun、kappaB)。最后，将探讨抑制性递质对反式激活因子的影响；SRIF和GABA的作用将通过潜在的模仿与已建立的受体选择性图谱的类似物与特定的受体亚型相关。我们的结果应该揭示SRIF和GABA限制神经胶质细胞产生炎性细胞因子的可能细胞机制。虽然一度被认为只有中枢神经系统中的保护性细胞成分，但激活的星形胶质细胞和小胶质细胞在AD期间会带来致命的神经毒性侮辱。了解神经递质可以阻止这种毒性神经胶质细胞激活的分子机制将为药物治疗神经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.