LYMPHOCYTE SIGNALLING PATHWAYS INVOLVING NUCLEAR FACTOR KAPPA B REGULATORS

几种淋巴因子基因的调节依赖于10个碱基的DNA 序列命名为kappaB。此外，最近有证据表明， 与该序列结合的因子relA的表达是重要的 保护细胞免受程序性细胞死亡。我们一直在 使用几种方法调查其在这些过程中的作用。 首先，我们一直在研究淋巴细胞的程序性细胞死亡。 KappaB序列激活受损的小鼠 一种主要的干扰I-kappaB调节蛋白。初步 结果表明，这些小鼠的T细胞可能更容易受到感染 致死的肿瘤坏死因子，这是特别是 CD8+T细胞明显增多。另外，我们发现的数据表明 IL-4的产生，一种参与防御的淋巴因子 细胞外寄生虫可能受到损害。这些实验是 目前正在重复。如果得到证实，佐证将来自 检测在小鼠体内重组的缺少RELA的免疫系统 无法制造出自己的T细胞。与这些实验相关 是最近的一项倡议，目的是表征 CCR5趋化因子受体启动子。这种受体已经被证明 作为感染细胞的必需的共同受体 HIV的嗜巨噬细胞毒株。这种共受体可能强烈地 受CD28刺激的影响，这可能是由于 CCR5启动子上的核因子-kappaB。 进一步的一系列实验旨在研究这种联系 死亡和细胞凋亡的研究才刚刚开始。曾经有过 文献中关于死亡受体Fas可以激活的建议 核因子-kappaB，但其生理意义尚不清楚。我们 假设Fas分子的低水平激活反过来可以， 激活核因子-kappaB，促进细胞存活。使用敏感的记者 构造，我们现在正在调查 假想的激活发生了。如果取得了积极的结果，我们 然后调查这个信号是否有可能提供 对其他机制引起的程序性细胞死亡的保护。

Regulation of genes for several lymphokines depend on a 10 bp DNA sequence termed kappaB. In addition, it has recently been shown that expression of the factor RelA that binds to this sequence is important in protecting cells from programmed cell death. We have been investigating its role in these processes using several approaches. First, we have been examining programmed cell death in lymphocytes of mice that are impaired in their activation of the kappaB sequence due to a dominant interfering I-kappaB regulatory protein. Preliminary results suggest that the T-cells from these mice may be more susceptible to death induced by tumor necrosis factor, and that this is particularly striking in CD8+ T-cells. Separately, we have found data that suggest that production of IL-4, a lymphokine involved in defense against extracellular parasites may be impaired. These experiments are currently being repeated. If verified, corroboration will come from examining an immune system lacking RelA that is reconstituted in mice that are unable to make their own T-cells. Related to these experiments is a recent initiative to characterize a RelA binding site in the promoter of the CCR5 chemokine receptor. This receptor has been shown to serve as an obligatory co-receptor for the infection of cells with the macrophage-tropic strains of HIV. This co-receptor may be strongly influenced by CD28 stimulation and this could be due to the effect of NF-kappaB on the CCR5 promoter. A further series of experiments designed to investigate the association of death and apoptosis has just been started. There have been suggestions in the literature that the death receptor Fas can activate NF-kappaB, but the physiologic significance of this is unclear. We hypothesize that low level activation of the Fas molecule can, in turn, activate NF-kappaB, promoting cell survival. Using sensitive reporter constructs, we are now investigating the extent to which the hypothesized activation occurs. If positive results are obtained, we will then investigate the potential for this signal to provide protection against programmed cell death induced by other mechanisms.