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

描述（由申请人提供）：已知白细胞介素-12（IL-12）是活化树突状细胞（DC）、巨噬细胞和嗜中性粒细胞的产物。DC在与T细胞相互作用期间产生IL-12的能力对于建立保护性Th 1应答是必不可少的。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抗性是必不可少的，如在用细菌、细胞内原生动物和真菌病原体进行的许多感染研究中所证明的。弓形虫是IL-12最有效的诱导剂之一，并且已经确定这种有效的IL-12产生依赖于TLR 11活化。目前还不清楚TLR 11的活化如何产生与任何其他已知TLR相比如此丰富的IL-12产生，但产生适量的其他促炎细胞因子如IL-6和TNF。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IL-12的产生。本申请的目的是确定IL-12的产生与各种DC亚群中的其他TLR相比如何受TLR 11调节，这是追求该目标的下一步。在拟议的研究中，将通过分析TLR 11信号通路，对先天免疫细胞产生高水平IL-12的要求进行系统研究。我们期望提供开发策略所需的知识，这些策略将允许靶向DC中的IL-12产生，DC是免疫系统的主要哨兵和有吸引力的基于细胞的治疗性疫苗候选物。 由树突状细胞（DC）产生的IL-12在驱动抗微生物应答和肿瘤监测中起主导作用。DC IL-12的产生主要由Toll样受体调节。这一提议是重要的，因为它有望获得开发策略所需的知识，这些策略将允许靶向DC中的IL-12产生，DC是免疫系统的主要哨兵和有吸引力的基于细胞的治疗性疫苗候选物

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