科研之友
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摘要
Macrophages (Mempty sets) are sentinels of the immune system that use pattern recognition receptors such as Toll-like receptors (TLR) to detect invading pathogens and immune receptors such as Fc gamma R to sense the host's immune state. Crosstalk between these two signaling pathways allows the Mempty set to tailor the cell's overall response to prevailing conditions. However, the molecular mechanisms underlying TLR-Fc gamma R crosstalk are only partially understood. Therefore, we employed an immunologically-relevant Mempty set stimulus, an inactivated gram-negative (b) under bar acterium that bears (TLR2) under bar agonists but no TLR4 agonist (iB(TLR2)) opsonized with a monoclonal antibody (mAb-iB(TLR2)), as a tool to study Fc gamma R regulation of TLR2-driven production of IL-6, a key inflammatory cytokine. We chose this particular agonist as an investigational tool because Mempty set production of any detectable IL-6 in response to mAbiBTLR2 requires both TLR2 and Fc gamma R signaling, making it an excellent system for the study of receptor synergy. Using genetic, pharmacological and immunological approaches, we demonstrate that the murine Mempty set IL-6 response to mAb-iB(TLR2) requires activation of both the TLR/NF-kappa B and Fc gamma R/ITAM signaling pathways. mAb-iB(TLR2) engagement of TLR2 drives NF-kappa B activation and up-regulation of IL-6 mRNA but fails to result in IL-6 cytokine production/release. Here, Src family kinase-driven Fc gamma R ITAM signaling is necessary to enable IL-6 mRNA incorporation into polysomes and translation. These results reveal a novel mechanism by which Fc gamma R ITAM signaling synergizes with TLR signaling, by "licensing" cytokine mRNA ribosome binding/translation to drive a strong murine Mempty set cytokine response.
- 出版日期2018-7-19
