LPS Regulation of Macrophage Function

描述(由申请人提供)：先天性免疫细胞缺乏适应性免疫系统的精致特异性，但为了以有节制的方式做出反应，它们必须能够对特定病原体的反应进行量身定制。这些细胞进化出模式识别受体(PRR)，识别宿主中没有的微生物特有的保守分子模式。通过识别PRRs的特定模式组合，宿主细胞可以对入侵者进行表型鉴定并做出适当的反应。Toll样受体，或称TLRs，是典型的模式识别受体。TLR激活对宿主防御至关重要；然而，如果不严格控制，就会接踵而至的炎症性疾病。虽然对TLRs激活的信号通路了解很多，但对减弱炎症反应的抑制机制知之甚少。我们已经发现，由内毒素诱导的巨噬细胞转录因子ATF3是TLR4诱导的IL-6、IL-12和TNF转录的有效衰减剂。与此一致的是，ATF3基因缺失的小鼠对内毒素诱导的休克和沙门氏菌感染高度敏感。我们建议定义ATF3衰减TLR-信号的机制。答：我们将首先确定ATF3翻译后修饰在调节ATF3/HDAC1相互作用、染色质重塑和转录控制中的作用。我们将描述ATF3与核因子？B和C/EBP？相互作用的机制。协调细胞因子基因的转录。C.我们将研究ATF3在小鼠先天免疫中的作用。版面总结。正在研究的蛋白质在调节人类的炎症和免疫反应方面起着关键作用。它们指示身体有效地对抗传染病，了解它们的功能将使我们能够制造更好的疫苗。然而，这些分子是一把双刃剑。当它们功能不正常时，它们会导致炎症和自身免疫性疾病。了解这种情况是如何发生的，将导致设计和生产更好的药物来治疗类风湿性关节炎等疾病。

DESCRIPTION (provided by applicant): Innate immune cells lack the exquisite specificity of the adaptive immune system, yet in order to respond in a measured way they must be able to tailor their response to specific pathogens. These cells have evolved pattern recognition receptors (PRRs) that recognize conserved molecular patterns characteristic of the microbe which are not found within the host. Recognition of the specific combination of patterns by the PRRs allows the host cell to phenotype the invader and to respond appropriately. The Toll-like receptors, or TLRs, are the prototypic pattern recognition receptors. TLR activation is critical for host defense; however, if it is not tightly regulated inflammatory disease ensues. While much is known about the signaling pathways that are activated by TLRs, little is known about the inhibitory mechanisms that attenuate the inflammatory response. We have found that a transcription factor, ATF3, that is induced by LPS in macrophages is a potent attenuator of TLR4-induced transcription of IL-6, IL-12, and TNF. Consistent with this, ATF3 null mice are highly susceptible to LPS-induced shock and to infection with Salmonella. We propose to define the mechanism by which ATF3 attenuates TLR-signaling. A. We will first define the role of ATF3 posttranslational modifications in the regulation of ATF3/HDAC1 interactions, chromatin remodeling, and transcriptional control. B. We will delineate the mechanism by which ATF3 interacts with NF-?B, and C/EBP? to coordinate the transcription of cytokine genes. C. We will examine the role of ATF3 in innate immunity in mice. Lay summary. The proteins that are being investigated have a pivotal role in regulating the inflammatory and immune response in people. They instruct the body to effectively combat infectious disease, and an understanding of their function will permit us to make better vaccines. However, these molecules are a two-edged sword. When they function incorrectly they lead to inflammatory and autoimmune diseases. Understanding how this happens will lead to the design and production of better drugs for diseases such as rheumatoid arthritis.