IMMUNE CYTOKINE REGULATION OF NEUROTRANSMITTER PHENOTYPE

神经科学的中心问题之一与机制有关 神经系统对环境做出反应的能力 刺激既是正常的也是创伤的。新生儿优秀症 大鼠颈(交感)神经节(SCG) 仔细观察其改变其神经递质补体的能力 对不断变化的环境信号的反应。在一个戏剧性的例子中 神经递质可塑性、P物质及其编码的mRNA 突触前电刺激时SCG内前激素前体增多 活动被撤回。由于SP的增加是在面对 对神经节的损伤(即，去传入)，我们试图确定 在损伤过程中释放的免疫细胞因子是否在 规范SP的增加。 在初步研究中，我们发现白介素1(IL-1) 显著增加SP及其前激素的编码基因 培养的(受损的)交感神经节中的前体；然而，这不是 IL-1对神经元的直接作用，但涉及IL-1 诱导白血病抑制因子(LIF)、睫状神经营养因子 因子(CNTF)，可能还有其他分子。这些，反过来，工作在 神经元对SP的升高起作用。 因为SP对免疫系统有多种刺激作用， 这些数据表明，SP在神经免疫调节中起着关键作用 外围的通信。 这些发现提出的几个问题将在本报告中得到解决 求婚。具体地说，我们计划确定哪些细胞携带IL-1 受体和哪些是中间分子的来源； IL-1诱导LIF和CNTF的新生物合成 突触前电活动导致神经元产生IL-1； 肿瘤坏死因子-α，另一种SP诱导的巨噬细胞产物， 通过与IL-1类似的机制发挥作用； IL-1影响SP以外神经肽的生物合成；作用 IL-1诱导的SP促进细胞存活和/或分化的作用 交感神经节和/或促进免疫激活。

One of the central issues of neuroscience concerns the mechanisms underlying the ability of the nervous system to respond to environmental stimuli that are both normal and traumatic. The neonatal superior cervical (sympathetic) ganglion (SCG) of the rat has been heavily scrutinized for its ability to alter its neurotransmitter complement in response to changing environmental signals. In one instance of dramatic neurotransmitter plasticity, substance P (SP) and the mRNA coding for its prohormone precursor are increased in the SCG when presynaptic electrical activity is withdrawn. Since the increase in SP occurs in the face of damage (i.e., deafferentation) to the ganglion, we sought to determine whether immune cytokines, released during injury, played a role in regulating the increase in SP. In preliminary studies we have found that interleukin-1 (IL-1) substantially increases SP and the mRNA coding for its prohormone precursor in cultured (injured) sympathetic ganglia; however, this is not a direct action of IL-1 on neurons, but rather involves the IL-1 induction of leukemia-inhibitory factor (LIF), ciliary neuronotrophic factor (CNTF), and possibly other molecules. These, in turn, work on neurons to effect the increase in SP. Because SP exerts a variety of stimulatory actions on the immune system, these data suggest a pivotal role for SP in mediating neuroimmunological communication in the periphery. Several issues raised by these findings are to be addressed in this proposal. Specifically, we plan to determine which cells bear the IL-1 receptor and which are the source of the intermediate molecules; whether IL-1 induces new biosynthesis of LIF and CNTF; whether the loss of presynaptic electrical activity causes neurons to elaborate IL-1; whether tumor necrosis factor-alpha, another SP-inducing macrophage product, operates through mechanisms similar to those of IL-1; whether the biosynthesis of neuropeptides other than SP is affected by IL-1; the role of IL-1-induced SP in promoting the survival and/or differentiation of sympathetic ganglia and/or in promoting immune activation.