CYTOKINE REGULATION OF PROENKEPHALIN GENE EXPRESSION

细胞因子，长期以来一直被认为是调节免疫功能， 造血作用，最近已经显示出对 神经基因表达、增殖和存活。的确， 分类为细胞因子和神经营养因子的肽之间的关系， 变得越来越模糊。例如，细胞因子如白细胞介素-1 =DF (IL-1=DF），其作用于外周以调节免疫应答， 调节整个器官的适应性， 感染炎症和压力其他细胞因子，如白血病 抑制因子（LIF），似乎参与了适应的 神经系统损伤，并密切相关的因素参与， 神经元存活和表型确定。迄今所知甚少 细胞因子调节转录的分子机制 关于神经基因之间的相互作用， 细胞因子和神经递质信号通路。前脑啡肽基因， 编码阿片肽甲硫氨酸和亮氨酸脑啡肽， 神经系统转录调控的重要模型; 因此，对前脑啡肽原基因的结构和调控有很多了解。 因为脑啡肽原基因的表达不仅受到 神经递质和药物滥用，而且还通过多种细胞因子， 包括IL-1=DF和LIF，我们建议使用脑啡肽原基因， 作为一个模型，以阐明这些代表性的分子作用， 和神经系统中生理上重要的细胞因子。我们 建议使用神经胶质和下丘脑神经元的原代培养物， 下丘脑在完整的动物，包括转基因小鼠，研究 细胞因子信号通路，它们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。所得 此外，信息还应有助于我们了解 神经系统和免疫系统之间的相互作用， 药物滥用对这些相互作用的潜在影响，如可能发生在 患有艾滋病的吸毒者

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.