Molecular mechanisms of IL-1R-TLR mediated signaling

项目1的目标是了解IL-IR-Toll样蛋白的分子机制 受体(TLR)信号转导调节动脉粥样硬化的发生发展。遗传和 我们和其他人的生化研究表明，IL-1R-TLRs诱导TAK1(TGFp激活的激酶1)-和 MEKK3(MAP KEK3)依赖的通路，涉及由以下组织的激酶级联 多个适配分子形成并行和顺序的信号复合体，导致激活 转录因子NFkB。IL-1R-TLRs还介导细胞因子和趋化因子的mRNA稳定， 对于有效的炎症反应是必不可少的。我们最近发现IL-1R-TLR介导的TAK1- 依赖于NFkB的激活与mRNA稳定途径相耦合，以诱导强健的生产 细胞因子和趋化因子。另一方面，IL-1-R-TLR介导的MEKKS依赖途径是 从mRNA稳定途径解偶联，只能诱导不是 受mRNA稳定性(包括抑制分子A20和IkBA)调节，发挥全面抑制作用 对炎症基因表达的影响。基于这些发现，我们假设IL-1R-TLRs触发 TAK1依赖的NFkB激活与mRNA稳定途径偶联的炎症反应 诱导细胞因子和趋化因子的强劲产生。IL-1R-TLR介导的MEKK3依赖的NFkB 活化途径通过解偶联基因转录抑制全身性炎症反应 通过产生抑制信号分子来抑制细胞因子的产生 和趋化因子。为了验证这一假说，我们建议阐明协调- 全反式调节IL-1R-TLR诱导的TAK1依赖的NFkB活化和mRNA稳定途径(目的 1)阐明了IL-1R-TLR诱导MEKKS依赖的NFkB活化的分子机制及其作用 在解偶联基因转录从mRNA稳定(目标2)；并研究病理生理 IL-1R-TLR诱导的TAK1与MEKKS依赖的NFkB激活及mRNA稳定性的作用 信号在动脉粥样硬化发展中的级联作用(目标3)。 相关性(请参阅说明)： 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，有助于解释NFkB如何调节肿瘤的发病、进展和 消退血管疾病的炎症，如动脉粥样硬化。我们的长期目标是 开发更有效的抗炎和抗动脉粥样硬化小分子药物。

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.