Tumor-secreted factors induce IL-1β maturation via the glucose-mediated synergistic axis of mTOR and NF-κB pathways in mouse macrophages

초록

Macrophages are one of the major cell types that produce IL-1 beta. IL-1 beta maturation occurs via inflammasome activation, and mature IL-1 beta is then released from the cell. Secreted IL-1 beta mediates inflammatory reactions in various pathological environments, such as those in infectious, autoimmune, and cancerous diseases. Although the mechanism of IL-1 beta production has been discovered in infectious and autoimmune diseases, its production mechanism in the tumor microenvironment is unclear. Therefore, the mechanism of IL-1 beta production in macrophages in the tumor microenvironment was investigated in this study. First, bone marrow- derived macrophages obtained from C57BL/6 mice were treated with B16F10 tumorconditioned media (TCM) in vitro. TCM increased the levels of IL-1 beta via glucose-mediated activation of the inflammasome. Moreover, TCM enhanced the activation of both NF-kappa B and mTOR pathways in a glucose-dependent manner. In particular, the expression levels of mTORC1 component proteins were dependent on the TCM-induced activation of NF-kappa B signaling. In addition, TCM affected ASC-ASC interactions through increasing intracellular reactive oxygen species levels. Finally, glucose inhibition by inoculation with 2-deoxy-D-glucose in vivo decreased the IL-1 beta levels in both the blood and tumor region of B16F10-bearing C57BL/6 mice relative to those in PBS-injected tumor-bearing mice. These results suggest that glucose supplied from blood vessels might be important for IL-1 beta production in tumor-associated macrophages via the integrated signals of the NF-kappa B and mTOR pathways in the tumor microenvironment.

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