Effects of the herbicide, propanil, on T cell signaling

描述（由申请人提供）：丙烯是一种紧急除草剂，广泛用于水稻。水稻含有高水平的芳基酰胺酶，这使得它可以解毒丙烯，因此，在一个生长季节可以多次使用这种除草剂，每年大约使用900万磅丙烯。由于其高使用率，这种除草剂对整个美国的施用者，装载机和农场家庭构成了主要的暴露威胁。我们之前已经证明，在小鼠体内给药以及添加到小鼠和人类T细胞培养物中时，丙烯会导致细胞因子产生减少。我们的数据表明，这至少部分是由于其干扰启动最佳转录所需的细胞信号传导过程的能力。我们的数据显示，这导致至少三个转录因子，NF-AT， NF-KB和AP- 1， IL-2基因转录所需的核水平降低。自上次提交以来，已经收集了足够的额外数据，以便对这些转录因子的变化进行统计分析。对这些结果的解释至关重要的是，除了这些转录因子水平的显著变化之外，高峰生产的年表也发生了显著变化。已发表的数据表明，这三种转录因子必须同时存在，才能产生最佳的细胞因子21;40;77。本提案将通过彻底检查启动IL-2转录所需的信号通路来研究这种对人类T细胞的作用机制。这将通过三个具体目标来实现：1)确定丙烯在人类T淋巴细胞中影响c-jun激活途径的步骤。2)确定丙烯对导致NF-AT激活的早期受体介导的信号事件的影响。3)确定丙烯对NFkB信号通路的影响。

DESCRIPTION (provided by applicant): Propanil is a post-emergent herbicide that is used extensively on rice. Rice has high levels of arylamidase, which allows it to detoxify the propanil, thus, making it possible to apply this herbicide several times during a growing season and approximately 9 million pounds of propanil are used annually. Because of its high rate of use, this herbicide presents a major exposure threat to applicators, loaders, and farm families throughout the USA. We have previously shown that propanil causes reduced cytokine production when administered in vivo to mice and when added to both murine and human T cell cultures. Our data indicate that this is at least partially due to its ability to interfere with cellular signaling processes required to initiate optimal transcription. Our data shows that this results in reduced nuclear levels of at least three transcription factors, NF-AT, NF-KB and AP- 1, required for IL-2 gene transcription. Since the last submission, sufficient additional data has been collected to allow statistical analysis of the changes in these transcription factors. Of critical importance in the interpretation of these results is that in addition to the significant changes in the levels of these transcription factors is the noted change in chronology of peak production. Published data indicates that all three transcription factors must be present at the same time for optimal cytokine production 21;40;77. This proposal will investigate the mechanism of this effect on human T cells by thoroughly examining the signaling pathways required to initiate IL-2 transcription. This will be accomplished through three specific aims: 1) Determine the steps in the c-jun activation pathway that propanil affects in human T lymphocytes. 2) Determine the effect of propanil on early receptor-mediated signaling events that lead to NF-AT activation. 3) Determine the step(s) in the NFkB signaling pathway affected by propanil.