Abstract
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 mechanism of IL-1β 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-1β via glucose-mediated activation of the inflammasome. Moreover, TCM enhanced the activation of both NF-κB 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-κB 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-1β 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-1β production in tumor-associated macrophages via the integrated signals of the NF-κB and mTOR pathways in the tumor microenvironment.
Highlights
Tumors are formed by an accumulation of abnormal cells and are uncommon tissues composed of tumor cells and extracellular matrix (ECM), epithelial cells, endothelial cells, adipocytes, fibroblasts and immune cells [1]
Secreted IL-1β levels and ASC-ASC interactions were increased in the 25% tumorconditioned media (TCM) group compared to those in the other groups (Panel B and C in S1 Fig). 25% TCM stimulation in medium with sufficient nutrients resulted in higher levels of mature IL-1β via enhanced inflammasome activation in macrophages (S1 Fig)
Positive effects of IL-1β produced by macrophages on tumorigenesis and angiogenesis have been reported [36, 37], but the mechanism of IL-1β production is unknown in the tumor microenvironment
Summary
Tumors are formed by an accumulation of abnormal cells and are uncommon tissues composed of tumor cells and extracellular matrix (ECM), epithelial cells, endothelial cells, adipocytes, fibroblasts and immune cells [1]. Lactic acid produced by tumor cells can induce polarization from M0 to M2-like macrophages through inducing the expression of vascular endothelial growth factor (VEGF) and arginase-1 [3]. HMGB1 released from tumor cells can increase the pro-tumoral activities of macrophages via a RAGE-dependent mechanism [5]. Tumor-associated macrophages have characteristics of the M2-like phenotype, this cell population can produce pro-inflammatory cytokines, such as IL-1β, depending on the conditions of the tumor microenvironment [7]. Tumor secreted factors, including lactate and HMGB1, induced macrophage polarization to M2 type, but these factors induced IL-1β production in the cells [8, 9]. To determine the mechanisms of IL-1β production through inflammasome activation in the tumor microenvironment, bone marrow-derived macrophages (BMDMs) exposed to B16F10-conditioned media were investigated
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