LPS Regulation of Macrophage Function

描述（由申请人提供）：先天免疫细胞缺乏适应性免疫系统的精确特异性，但为了以可测量的方式应答，它们必须能够定制它们对特定病原体的应答。这些细胞已经进化出模式识别受体（PRR），其识别在宿主内未发现的微生物的保守分子模式特征。PRR对特定模式组合的识别允许宿主细胞对入侵者进行表型化并适当地响应。Toll样受体或TLR是原型模式识别受体。TLR激活对于宿主防御至关重要;然而，如果它不被严格调控，则会引发炎症性疾病。虽然对TLR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，巨噬细胞中由LPS诱导的转录因子ATF 3是TLR 4诱导的IL-6、IL-12和TNF转录的有效衰减剂。与此一致，ATF 3敲除小鼠对LPS诱导的休克和沙门氏菌感染高度敏感。我们建议定义ATF 3减弱TLR信号传导的机制。A.我们将首先定义的作用，ATF 3/HDAC 1相互作用，染色质重塑和转录控制的调节中的ATF 3翻译后修饰。B。我们将描绘ATF 3与NF-？B和C/EBP？以协调细胞因子基因的转录。C.我们将研究ATF 3在小鼠先天免疫中的作用。简单总结。正在研究的蛋白质在调节人体炎症和免疫反应中起着关键作用。它们指导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。当它们功能不正确时，它们会导致炎症和自身免疫性疾病。了解这是如何发生的将导致设计和生产更好的药物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.