EARLY EVENTS IN ACCESSORY CELL ACTIVATION

单核细胞和巨噬细胞功能研究中的一个中心挑战 免疫系统正在理解调节它们的早期事件 激活。这些辅助细胞在抗原处理过程中起着重要作用。 和呈现，分泌几种有效的多肽因子，以及 支持T淋巴细胞的增殖和活化。几秒钟 信使系统可以传输各种刺激信号，以便 产生适当的细胞反应，例如产生 特定的早期激活基因产物。这项提议的目标是 为加深对单核/巨噬细胞活化的理解 传递刺激信号的核调节蛋白的研究进展 并控制早期激活基因的表达。实验将会 关注单因子白介素1α(IL-1α)和 白细胞介素1β(IL-1β)作为早期事件研究的模型系统 在单核细胞激活中。这些重要的免疫调节多肽是 早期事件研究的候选对象，因为它们迅速和 在单核/巨噬细胞刺激后协同表达。这个 这些研究的长期目标是(1)识别和提纯 调节IL-1表达的核调节蛋白，(2)评估 这些蛋白的功能作用，(3)确定巨噬细胞如何 激活因子，如干扰素和集落刺激因子 可以通过影响这些核蛋白来增强IL-1的表达，并且 (4)研究它们的活动如何受到第二信使信号的调节 和/或特定的细胞内抑制物。这些研究应该导致一个 更好地理解各种刺激信号的机制 被巨噬细胞/单核细胞用来产生特定的DNA蛋白 相互作用并导致特定早期事件的启动 激活。这些信息对于理解 几种自身免疫性和炎症性疾病的病因学可能涉及 单核细胞的异常表达。此外，激活 HIV感染的巨噬细胞可导致两种病毒基因的共表达 产品和IL-1，从而了解调节早期事件 IL-1的表达可能有助于揭示HIV感染的病理机制 巨噬细胞。

A central challenge in the study of monocyte and macrophage function in the immune system is understanding the early events which regulate their activation. These accessory cells play a major role in antigen processing and presentation, the secretion of several potent polypeptide factors, and the support T lymphocyte proliferation and activation. Several second messenger systems may transmit a variety of stimulatory signals in order to generate an appropriate cellular response, such as the production of specific early-activation gene products. The objective of this proposal is to further the understanding of monocyte/macrophage activation through the study of nuclear regulatory proteins which transduce stimulatory signals and control the expression of early-activation genes. Experiments will focus on the expression of the monokines interleukin 1alpha (IL-1alpha) and interleukin 1beta (IL-1beta as a model system for the study of early events in monocyte activation. These important immunoregulatory polypeptides are candidates for the study of early events since they are rapidly and coordinately expressed following monocyte/macrophage stimulation. The long-range goals of these studies are (1) to identify and purify the nuclear regulatory proteins which modulate IL-1 expression, (2) to evaluate the functional role of these proteins, (3) to determine how macrophage activating factors such as gamma interferon and colony stimulating factors can augment IL-1 expression through effects on these nuclear proteins, and (4) to examine how their activity is regulated by second messenger signals and/or specific intracellular inhibitors. These studies should lead to a greater understanding of the mechanism by which various stimulatory signals are utilized by the macrophage/monocyte to generate specific DNA-protein interactions and lead to the initiation of specific early events during activation. This information has particular value in understanding the etiology of several autoimmune and inflammatory diseases which may involve the aberrant expression of monokines. Furthermore, the activation of HIV-infected macrophages can lead to the co-expression of both viral gene products and IL-1, thus an understanding of the early events which regulate IL-1 expression may shed light on the pathology of HIV-infected macrophages.