The indirect antiangiogenic effect of IL-37 in the tumor microenvironment

Abstract

IL-37, a newly identified IL-1 family cytokine, has been shown to play an important role in inflammatory diseases, autoimmune diseases, and carcinogenesis. IL-37 has been suggested to suppress tumoral angiogenesis, whereas some publications showed that IL-37 promoted angiogenesis through TGF-signaling in both physiologic and pathologic conditions. Therefore, the function of IL-37 in tumoral angiogenesis is not clear and the underlying mechanism is not known.In this current study, we investigated the direct role of IL-37 on endothelial cells, as well as its indirect effect on angiogenesis through functioning on tumor cells both in vitro and in vivo. We found that IL-37 treatment directly promoted HUVEC migration and tubule formation, indicating IL-37 as a proangiogenic factor. Surprisingly, the supernatants from IL-37 overexpressing tumor cell line promoted HUVEC apoptosis and inhibited its migration and tubule formation. Furthermore, we demonstrated that IL-37 suppressed tumor angiogenesis in a murine orthotopic hepatocellular carcinoma model, suggesting its dominant antiangiogenesis role in vivo. Moreover, microarray and qPCR analysis demonstrated that IL-37 reduced the expressions of proangiogenic factors and increased the expressions of antiangiogenic factors by tumor cells. Matrix metalloproteinase (MMP)2 expression was significantly decreased by IL-37 in both cell lines and murine tumor models. MMP9 and vascular endothelial growth factor expressions were also reduced in murine tumors overexpressing IL-37, as well as in cell lines overexpressing IL-37 under hypoxic conditions. In conclusion, although IL-37 could exert direct proangiogenic effects on endothelial cells, it plays an antiangiogenic role via modulating proangiogenic and antiangiogenic factor expressions by tumor cells in the tumor microenvironment.

Current Understanding of IL-37 in Human Health and Disease

“…However, the opposite effect is observed when HUVECs are treated with the supernatant from tumor cell lines overexpressing IL-37, since they undergo apoptosis and their migration and tubule formation is suppressed (79). As regard the in vivo effect, IL-37 inhibits tumor angiogenesis in the murine orthotopic hepatocellular carcinoma model, suggesting that it can induce an antiangiogenic effect (79). IL-37 reduces the expression of proangiogenic factors and increases the one of antiangiogenic factors in tumor cells (79), as well as decreases matrix metalloproteinase (MMP) 2 expression in SK-Hep-1 and SMMC-7721 cell lines overexpressing IL-37 and murine tumor models (79).…”

“…The protective effect of IL-37 against various cancer types depends on tumor type and stage and IL-37 isoforms. IL-37 treatment increases human umbilical vein endothelial cells (HUVEC) migration and tubule formation, suggesting that IL-37 is a pro-angiogenic factor (79). However, the opposite effect is observed when HUVECs are treated with the supernatant from tumor cell lines overexpressing IL-37, since they undergo apoptosis and their migration and tubule formation is suppressed (79).…”

“…IL-37 treatment increases human umbilical vein endothelial cells (HUVEC) migration and tubule formation, suggesting that IL-37 is a pro-angiogenic factor (79). However, the opposite effect is observed when HUVECs are treated with the supernatant from tumor cell lines overexpressing IL-37, since they undergo apoptosis and their migration and tubule formation is suppressed (79). As regard the in vivo effect, IL-37 inhibits tumor angiogenesis in the murine orthotopic hepatocellular carcinoma model, suggesting that it can induce an antiangiogenic effect (79).…”

“…IL-37 reduces the expression of proangiogenic factors and increases the one of antiangiogenic factors in tumor cells (79), as well as decreases matrix metalloproteinase (MMP) 2 expression in SK-Hep-1 and SMMC-7721 cell lines overexpressing IL-37 and murine tumor models (79). The expression of MMP9 and vascular endothelial growth factor (VEGF) is also decreased in SK-Hep-1-venus and SK-Hep-1-IL-37 cells overexpressing IL-37 and murine tumors overexpressing IL-37 under hypoxic conditions (79). Moreover, tumor-associated macrophages (TAMs) promote tumor progression.…”

IL-1 Family Antagonists in Mouse and Human Skin Inflammation

“…Finally, while many studies point toward a broad inhibitory activity of IL-37 in innate inflammatory responses, effects of IL-37 on adaptive immunity, metabolism, angiogenesis, cell proliferation, and migration have also been reported (247)(248)(249)(250)(251)(252)(253)(254)(255).…”