LYMPHOCYTE SIGNALLING PATHWAYS INVOLVING NUCLEAR FACTOR KAPPA B REGULATORS

几种淋巴因子的基因调控依赖于一个10 bp的DNA 序列称为kappaB。 此外，最近的研究表明， 与该序列结合的因子RelA的表达是重要的 保护细胞免于程序性细胞死亡 我们一直 研究其在这些过程中的作用，使用几种方法。 首先，我们已经研究了淋巴细胞中的程序性细胞死亡， 小鼠在其kappaB序列的激活中受损， 显性干扰I-κ B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 肿瘤坏死因子引起的死亡，这是特别重要的， 在CD 8 + T细胞中显著。 另外，我们发现数据表明 IL-4是一种淋巴因子， 细胞外寄生物可能受损。 这些实验 目前正在重复。 如果得到证实，佐证将来自 检测缺乏RelA的免疫系统， 无法制造自己的T细胞 与这些实验相关的 是一个最近的倡议，以表征RelA结合位点在 CCR 5趋化因子受体的启动子。 这种受体已经被证明 作为感染细胞的强制性辅助受体， 嗜巨噬细胞的HIV病毒株 这种辅助受体可能强烈地 受CD 28刺激的影响，这可能是由于 CCR 5启动子上的NF-κ B。 进一步的一系列实验旨在研究 死亡和细胞凋亡才刚刚开始。 有 在文献中的建议，死亡受体Fas可以激活 NF-κ B，但其生理意义尚不清楚。 我们 假设Fas分子低水平活化，反过来， 激活NF-κ B，促进细胞存活。 使用敏感的报告基因 我们现在正在调查， 假设的激活发生。 如果获得了积极的结果，我们 然后将研究该信号提供 防止由其他机制诱导的程序性细胞死亡。

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.