Molecular pathways involved in TLR11 mediated IL-12 production by dendritic cells

TLR11 介导树突状细胞产生 IL-12 的分子途径

• 批准号: 7509644
• 负责人: Felix Yarovinsky
• 金额: $ 31.4万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7509644
• 关键词: Accounting; Adaptor Signaling Protein; Agonist; Automobile Driving; Bacteria; CD8B1 gene; Cells; Classification; Cryptosporidium; Data; Dendritic Cell Therapy; Dendritic Cells; Elements; Environment; Goals; Homologous Gene; Host resistance; Humpback Dolphins; IFN consensus sequence binding protein; Immune; Immune response; Immune system; Indium; Infection; Inflammatory; Interferons; Interleukin-12; Interleukin-6; Investigation; Knowledge; Laboratories; Ligands; Malaria; Mediating; Medical Surveillance; Molecular; NF-kappa B; Numbers; Parasites; Pathway interactions; Phosphotransferases; Plasmodium; Play; Population; Production; Protozoa; Public Health; Receptor Signaling; Recruitment Activity; Regulation; Research; Role; Sentinel; Signal Pathway; Signal Transduction; T-Lymphocyte; TNF gene; Testing; Toll-like receptors; Toxoplasma gondii; Work; antimicrobial; base; cytokine; innovation; macrophage; microbial; neutrophil; pathogen; profilin; response; therapeutic vaccine; tumor; tumor progression

DESCRIPTION (provided by applicant): lnterleukin-12 (IL-12) is known to be a product of activated dendritic cells (DC), macrophages and neutrophils. The ability of DC to produce IL-12 during interaction with T cells is essential for establishing a protective Th1 response. These pro-inflammatory functions of IL-12 are essential for the control of tumor progression and for host resistance to different types of infections, as was demonstrated in many infection studies performed with bacteria, intracellular protozoa and fungal pathogens. Toxoplasma gondii is one of the most potent inducers of IL-12 and it has been established that this potent IL-12 production depends upon TLR11 activation. At present it is unclear how activation of TLR11 yields such abundant IL-12 production in comparison with any other known TLRs, but modest amounts of other pro-inflammatory cytokines such as IL-6 and TNF. Our long term goal is to understand the mechanisms accounting for diversification of TLR effector functions with emphasis on selective IL-12 production by DC. The objective of this application, which is the next step in pursuit of that goal, is to determine how production of IL-12 is regulated by TLR11 in comparison with other TLRs in various DC subsets. In the proposed research the systemic investigation of requirements for high level IL-12 production by innate immune cells through the analysis of the TLR11 signaling pathways will be performed. We expect to provide knowledge needed to develop strategies that will allow targeting of IL-12 production in DC, the major sentinels of the immune system and attractive cell-based therapeutic vaccine candidates. PUBLIC HEALTH RELEVANCE IL-12 produced by dendritic cells (DC) plays a dominant role in driving antimicrobial responses and tumor surveillance. DC IL-12 production is primarily regulated by Toll-like receptors. This proposal is significant because it is expected to obtain knowledge needed to develop strategies that will allow targeting of IL-12 production in DC, the major sentinels of the immune system and attractive cell-based therapeutic vaccine candidates

说明(申请人提供)：白介素12(IL-12)是已知的由激活的树突状细胞(DC)、巨噬细胞和中性粒细胞产生的产物。DC在与T细胞相互作用过程中产生IL-12的能力对于建立保护性Th1反应是必不可少的。IL-12的这些促炎功能对于控制肿瘤进展和宿主对不同类型感染的抵抗力是必不可少的，正如许多针对细菌、细胞内原生动物和真菌病原体进行的感染研究所证明的那样。弓形虫是最有效的IL-12诱导剂之一，已证实这种有效的IL-12产生依赖于TLR11的激活。目前尚不清楚与其他已知的TLR相比，激活TLR11是如何产生如此丰富的IL-12的，但也有少量的其他促炎细胞因子，如IL-6和肿瘤坏死因子。我们的长期目标是了解TLR效应器功能多样化的机制，重点是DC选择性地产生IL-12。这项应用的目标是确定TLR11与不同DC亚群中其他TLR相比如何调节IL-12的产生，这是追求该目标的下一步。在拟议的研究中，将通过分析TLR11信号通路来系统地研究先天免疫细胞产生高水平IL-12的需求。我们期望提供所需的知识来开发策略，允许靶向DC产生IL-12，DC是免疫系统的主要哨兵，也是有吸引力的基于细胞的治疗性疫苗候选。 与公共健康相关由树突状细胞(DC)产生的IL-12在驱动抗菌反应和肿瘤监测方面发挥着主导作用。DC IL-12的产生主要受Toll样受体的调节。这项提议意义重大，因为它有望获得所需的知识，以制定策略，允许靶向DC产生IL-12，DC是免疫系统的主要哨兵，也是有吸引力的基于细胞的治疗性疫苗候选