Molecular mechanisms of IL-1R-TLR mediated signaling

IL-1R-TLR介导信号传导的分子机制

• 批准号: 8242732
• 负责人: Xiaoxia Li
• 金额: $ 26.11万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242732
• 关键词: Ablation; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Arterial Fatty Streak; Atherosclerosis; Biochemical; Biological; Blood Vessels; Cells; Cessation of life; Complex; Coupled; Coupling; Cytokine Stabilization; Data; Development; Event; Gene Expression; Gene Targeting; Generations; Genetic; Genetic Transcription; Goals; IRAK1 gene; IRAK2 gene; IRAK4 gene; Immune; Immune response; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Instruction; Interleukin-1; Interleukin-1 Receptors; Interleukins; Investigation; Lead; Lesion; MAP3K3 gene; Mediating; Messenger RNA; Modeling; Molecular; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phosphotransferases; Physiological; Play; Production; Receptor Signaling; Regulation; Resolution; Role; Severities; Signal Transduction; Signaling Molecule; Testing; Toll-like receptors; Vascular Diseases; base; chemokine; cytokine; human IRAK3 protein; in vivo; interleukin-1 receptor-associated kinase; mRNA Stability; macrophage; mouse model; pathogen; receptor; receptor-mediated signaling; small molecule; transcription factor

The goal of Project 1 is to understand the molecular mechanisms by which interleukin (IL)-IR-toll-like receptor (TLR) signaling modulates the development and pathogenesis of atherosclerosis. Genetic and biochemical studies by us and others revealed that IL-1R-TLRs induce TAK1 (TGFp-activated kinase 1)- and MEKK3 (MAP kinase kinase kinase 3)-dependent pathways, involving cascades of kinases organized by multiple adapter molecules into parallel and sequential signaling complexes, leading to activation of the transcription factor NFkB. IL-1R-TLRs also mediate mRNA stabilization of cytokines and chemokines, which is essential for effective inflammatory response. We have recently shown that IL-1R-TLR-mediated TAK1- dependent NFkB activation is coupled with the mRNA stabilization pathway to induce the robust production of cytokines and chemokines. On the other hand, the IL-1-R-TLR-mediated MEKKS-dependent pathway is uncoupled from mRNA stabilization pathway and is only able to induce expression of genes that are not regulated by mRNA stability (including inhibitory molecules A20 and IkBa), exerting an overall inhibitory effect on inflammatory gene expression. Based on these findings, we hypothesize that IL-1R-TLRs trigger inflammatory response by coupling TAK1-dependent NFkB activation with mRNA stabilization pathway to induce robust production of cytokines and chemokines. The IL-1R-TLR-mediated MEKK3-dependent NFkB activation pathway is inhibitory to the overall inflammatory response by uncoupling gene transcription from mRNA stabilization and by producing inhibitory signaling molecules that turn down production of cytokines and chemokines. To test this hypothesis, we propose to elucidate the molecular mechanisms that coordin- ately regulate IL-1R-TLR-induced TAK1-dependent NFkB activation and mRNA stabilization pathways (Aim 1); delineate molecular mechanisms for IL-1R-TLR-induced MEKKS-dependent NFkB activation and its role in uncoupling gene transcription from mRNA stabilization (Aim 2); and investigate the patho-physiological functions of IL-1R-TLR-induced TAK1- versus MEKKS-dependent NFkB activation and mRNA stability signaling cascades in the development of atherosclerosis (Aim 3). RELEVANCE (See instructions): NfkB is an important factor that regulates the inflammatory response in macrophages. Our studies will elucidate a new mechanism that will help to explain how NFkB regulates the onset, progression, and resolution of inflammation in vascular diseases such as atherosclerosis. Our long-term objective is to develop more effective anti-inflammatory and anti-atherogenic small molecule drugs.

项目1的目标是了解白细胞介素（IL）-IR-样toll样蛋白表达的分子机制。 TLR信号调节动脉粥样硬化的发展和发病机制。遗传和 我们和其他人的生化研究表明，IL-1 R-TLR诱导TAK 1（TGF β激活的激酶1）-和 MEKK 3（MAP激酶3）依赖性途径，涉及由以下组织的激酶级联： 多个衔接分子转化为平行和顺序的信号复合物，导致激活的 转录因子NF κ B。IL-1 R-TLR还介导细胞因子和趋化因子的mRNA稳定， 对有效的炎症反应至关重要。我们最近发现IL-1 R-TLR-介导的TAK 1- 依赖性NFkB活化与mRNA稳定化途径偶联，以诱导稳定的生产 细胞因子和趋化因子。另一方面，IL-1-R-TLR介导的MEKKS依赖性途径是 与mRNA稳定化途径解偶联，并且仅能够诱导不与mRNA稳定化途径偶联的基因的表达。 受mRNA稳定性（包括抑制性分子A20和IkBa）调节，发挥总体抑制作用， 影响炎症基因表达。基于这些发现，我们假设IL-1 R-TLRs触发 通过将TAK 1依赖性NF κ B活化与mRNA稳定化途径偶联， 诱导细胞因子和趋化因子大量产生。IL-1 R-TLR介导的MEKK 3依赖性NFkB 激活途径通过将基因转录从细胞因子中解偶联来抑制整体炎症反应。 mRNA的稳定和通过产生抑制性信号分子来降低细胞因子的产生 和趋化因子。为了验证这一假设，我们建议阐明协调的分子机制- IL-1 R-TLR介导的TAK 1依赖性NFkB激活和mRNA稳定通路的调控（目的 1）阐明IL-1 R-TLR诱导MEKKS依赖性NF κ B活化的分子机制及其作用 在解偶联基因转录从mRNA的稳定（目的2），并探讨病理生理 IL-1 R-TLR诱导的TAK 1与MEKKS依赖性NFkB活化和mRNA稳定性的功能 信号级联在动脉粥样硬化的发展（目的3）。 相关性（参见说明）： NfkB是调节巨噬细胞炎症反应的重要因子。我们的研究将 阐明一种新的机制，这将有助于解释NFkB如何调节发病，进展， 解决血管疾病如动脉粥样硬化中的炎症。我们长远的目标是 开发更有效的抗炎和抗动脉粥样硬化的小分子药物。