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

Ut Southwestern Medical Center, Dallas TX

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Abstract

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