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

描述（由申请人提供）：白细胞介素-12 （IL-12）已知是活化的树突状细胞（DC）、巨噬细胞和中性粒细胞的产物。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应答至关重要。正如许多细菌、细胞内原生动物和真菌病原体的感染研究所证明的那样，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至关重要。刚地弓形虫是最有效的IL-12诱导剂之一，并且已经确定这种有效的IL-12的产生依赖于TLR11的激活。目前尚不清楚与其他已知的tlr相比，TLR11的激活如何产生如此丰富的IL-12，但其他促炎细胞因子如IL-6和TNF的数量有限。我们的长期目标是了解TLR效应功能多样化的机制，重点是DC选择性产生IL-12。该应用程序的目标是实现这一目标的下一步，即确定与各种DC亚群中的其他tlr相比，TLR11如何调节IL-12的产生。在拟议的研究中，将通过分析TLR11信号通路对先天免疫细胞高水平IL-12产生的需求进行系统研究。我们期望提供开发策略所需的知识，以靶向DC中IL-12的产生，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候选疫苗。

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