CYTOKINE REGULATION OF PROENKEPHALIN GENE EXPRESSION

细胞因子，长期以来一直被认为可以调节免疫功能和 造血术，最近已被证明对 神经基因的表达、增殖和存活。事实上，边界是 在被归类为细胞因子和神经营养因子的多肽之间 变得越来越模糊。例如，细胞因子，如白介素1=df (IL-1=dF)作用于外周，调节免疫反应，作用 在下丘脑内调节整个组织的适应 感染、炎症和压力。其他细胞因子，如白血病 抑制因子(LIF)似乎参与了细胞的适应 神经系统的损伤，与参与的因素密切相关 神经元存活和表型测定。到目前为止，人们知之甚少 关于细胞因子调控转录的分子机制 神经基因之间的相互作用更是鲜为人知 细胞因子和神经递质信号通路。脑啡肽原基因， 编码甲硫氨酸和亮氨酸脑啡肽的阿片肽，作为 神经系统转录调控的重要模型； 因此，我们对脑啡肽原基因的结构和调控有了很多的了解。 因为前脑啡肽基因的表达不仅受 神经递质和药物的滥用，还受到多种细胞因子的影响， 包括IL-1=DF和LIF，我们建议使用前脑啡肽基因 AS=一个模型来解释这些代表的分子作用 神经系统中具有重要生理意义的细胞因子。我们 建议使用神经胶质细胞和下丘脑神经元的原代培养和 研究包括转基因小鼠在内的完整动物的下丘脑 细胞因子信号通路及其与神经递质的相互作用 信号通路以及阿片类药物对它们的调节。由此产生的 此外，信息还应有助于我们理解 神经系统和免疫系统之间的相互作用，以及 滥用药物对这些相互作用的潜在影响，如在 患有艾滋病的活跃的吸毒者。

Cytokines, which have long been known to regulate immune function and hematopoiesis, have recently been shown to exert powerful effects on neural gene expression, proliferation, and survival. Indeed the boundaries between peptides classified as cytokines and as neurotrophic factors has been increasingly blurred. For example, cytokines such as interleukin-1=DF (IL-1=DF) which act in the periphery to modulate the immune response, act within the hypothalamus to regulate overall organismic adaptations to infection, inflammation, and stress. Other cytokines, such as leukemia inhibitory factor (LIF), appear to be involved in the adaptation of the nervous system to injury, and are closely related to factors involved in neuronal survival and phenotype determination. Little is known to date about the molecular mechanisms by which cytokines regulate transcription of neural genes, and even less is known about the interactions among cytokine and neurotransmitter signaling pathways. The proenkephalin gene, which encodes the opioid peptides met- and leu-enkephalin, has served as an important model of transcriptional regulation in the nervous system; therefore much is known about proenkephalin gene structure and regulation. Because proenkephalin gene expression is regulated not only by neurotransmitters and drugs of abuse, but also by multiple cytokines, including both IL-1=DF and LIF, we propose to use the proenkephalin gene as = a model to elucidate the molecular actions of these representative and physiologically significant cytokines in the nervous system. We propose to use primary cultures of glia and hypothalamic neurons and the hypothalamus in intact animals, including transgenic mice, to study cytokine signalling pathways, their interactions with neurotransmitter signaling pathways, and their modulation by opioids. The resulting information should contribute, in addition, to our understanding of interactions between the nervous system and the immune system, and of the potential impact of drugs of abuse on these interactions, as may occur in active drug abusers with AIDS.