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

ABSTRACT: Macrophages are one of the major cell types that produce IL-1?. IL-1? maturation occurs via inflammasome activation, and mature IL-1? is then released from the cell. Secreted IL-1? mediates inflammatory reactions in various pathological environments, such as those in infectious, autoimmune, and cancerous diseases. Although the mechanism of IL-1? production has been discovered in infectious and autoimmune diseases, its production mechanism in the tumor microenvironment is unclear. Therefore, the mechanism of IL-1? 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 tumor-conditioned media (TCM) in vitro. TCM increased the levels of IL-1? via glucose-mediated activation of the inflammasome. Moreover, TCM enhanced the activation of both NF-?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-?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? 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? production in tumor-associated macrophages via the integrated signals of the NF-?B and mTOR pathways in the tumor microenvironment.

SUBMITTER: Woo Y

PROVIDER: S-EPMC6306269 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Woo Yunseo Y Kim Hyeran H Kim Keun-Cheol KC Han Jeong A JA Jung Yu-Jin YJ

PloS one 20181226 12

Macrophages are one of the major cell types that produce IL-1β. IL-1β maturation occurs via inflammasome activation, and mature IL-1β is then released from the cell. Secreted IL-1β mediates inflammatory reactions in various pathological environments, such as those in infectious, autoimmune, and cancerous diseases. Although the mechanism of IL-1β production has been discovered in infectious and autoimmune diseases, its production mechanism in the tumor microenvironment is unclear. Therefore, the ...[more]

PMID: 30586442

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Project description:Koumine (KM), one of the primary constituents of Gelsemium elegans, has been used for the treatment of inflammatory diseases such as rheumatoid arthritis, but whether KM impacts the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome remains unknown. This study aimed to explore the inhibitory effect of KM on NLRP3 inflammasome activation and the underlying mechanisms both in vitro using macrophages stimulated with LPS plus ATP, nigericin or monosodium urate (MSU) crystals and in vivo using an MSU-induced peritonitis model. We found that KM dose-dependently inhibited IL-1β secretion in macrophages after NLRP3 inflammasome activators stimulation. Furthermore, KM treatment efficiently attenuated the infiltration of neutrophils and suppressed IL-1β production in mice with MSU-induced peritonitis. These results indicated that KM inhibited NLRP3 inflammasome activation, and consistent with this finding, KM effectively inhibited caspase-1 activation, mature IL-1β secretion, NLRP3 formation and pro-IL-1β expression in LPS-primed macrophages treated with ATP, nigericin or MSU. The mechanistic study showed that, KM exerted a potent inhibitory effect on the NLRP3 priming step, which decreased the phosphorylation of IκBα and p65, the nuclear localization of p65, and the secretion of TNF-α and IL-6. Moreover, the assembly of NLRP3 was also interrupted by KM. KM blocked apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and its oligomerization and hampered the NLRP3-ASC interaction. This suppression was attributed to the ability of KM to inhibit the production of reactive oxygen species (ROS). In support of this finding, the inhibitory effect of KM on ROS production was completely counteracted by H2O2, an ROS promoter. Our results provide the first indication that KM exerts an inhibitory effect on NLRP3 inflammasome activation associated with blocking the ROS/NF-κB/NLRP3 signal axis. KM might have potential clinical application in the treatment of NLRP3 inflammasome-related diseases.

Dataset Information

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

Publications

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

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