REGULATION OF CYTOKINE GENE EXPRESSION BY P42/44 KINASES

在这个项目中解决的总体问题是确定 激活人肺泡巨噬细胞中细胞因子基因的机制 (AM)脓毒症引起的急性肺损伤内毒素（LPS）释放 在脓毒症期间，它是细胞因子产生的有效触发剂， 巨噬细胞在体内和体外。这一点的重要性体现在 观察到细胞因子在脓毒症期间释放， 抑制细胞因子预防脓毒症动物急性肺损伤 疾病的模型。一些研究表明，p38丝裂原 活化蛋白激酶（MAPK）途径是释放 单核细胞对内毒素的反应。没有研究确定 其他MAPK途径在响应LPS释放细胞因子中的作用。 本申请的重点是定义p42/44 MAPK的作用 p38 MAPK信号通路及其与p38 MAPK信号通路的相互作用 人AM中细胞因子基因表达对LPS的响应。在我们的研究中， 我们探索了新的观察结果，即p42/44和p38 MAPK都是 在人AM中最佳细胞因子基因表达所需的途径， 这些MAPK通路中的每一个都具有不同的 对细胞因子基因表达的影响。更加重视学习 与p42/44激酶通路有关，因为这种关系 LPS诱导的细胞因子基因表达的途径尚不明确。我们 还探讨了新的观察，即激活氧化剂， 信号和磷脂酰胆碱特异性磷脂酶C（PC-PLC） 调节p42/44 MAPK通路和细胞因子基因的激活 表情这些观察结果构成了目标1研究的基础。在aim中 2，我们探索新的研究，涉及这些MAPK通路的激活 调节细胞因子的活性转录因子的产生 基因表达。这个项目与其他项目密切互动， SCOR中的项目，并依赖它们来执行许多 问题研究该项目还需要临床核心和研究， 该项目与临床核心研究密切相关。虽然 本申请的研究直接涉及脓毒症诱导的急性肺 伤害，他们是新的研究，也提供了重要的基本线索， 了解巨噬细胞因子基因调控。

The overall question that is addressed in this project is to determine the mechanisms which activate cytokine genes in human alveolar macrophages (AM) during sepsis-induced acute lung injury. Endotoxin (LPS) is released during sepsis and it is a potent trigger for cytokine production by macrophages in vivo and in vitro. The importance of this is illustrated by the observation that cytokines are released during sepsis and that inhibition of cytokines prevents acute lung injury during sepsis in animal models of the disease. Several studies have shown that the p38 mitogen activated protein kinases (MAPK) pathway is essential for release of cytokines by monocytes in response to endotoxin. No studies have defined a role for other MAPK pathways in release of cytokines in response to LPS. The focus of this application is to define the role(s) of the p42/44 MAPK pathway and its interaction with the p38 MAPK pathway in regulating cytokine gene expression in human AM in response to LPS. In our studies, we explore the novel observation that both the p42/44 and p38 MAPK pathways are required for optimal cytokine gene expression in human AM in response to LPS and that each of these MAPK pathways has a different effect on cytokine gene expression. More emphasis is placed on studies relating to the p42/44 kinase pathway since the relationship of this pathway to LPS-induced cytokine gene expression is less well defined. We also explore the novel observations that activation of both an oxidant signal and a phosphatidylcholine-specific phospholipase C (PC-PLC) regulate activation of the p42/44 MAPK pathway and cytokine gene expression. These observations form the basis for studies in Aim 1. In Aim 2, we explore novel studies that relate activation of these MAPK pathways to the generation of active transcription factors that regulate cytokine gene expression. This project interacts, closely, with each of the other projects in the SCOR and is dependent on them to carry out many of the studies. The project also needs the Clinical Core and the studies in this project relate, closely, to studies in the Clinical Core. Although the studies in this application relate, directly, to sepsis-induced acute lung injury, they are novel studies that also provide important basic clues to understand macrophage cytokine gene regulation.