Interleukin 37 promotes angiogenesis through TGF-β signaling

Zhao, Mengmeng; Hu, Yu; Jin, Jiaqi; Yu, Ying; Zhang, Shanshan; Cao, Jingjing; Zhai, Yuanfen; Wei, Ran; Shou, Juanjuan; Cai, Wen; Liu, Shangfeng; Yang, Xiao‐Ping; Xu, Guo; Yang, Jianhua; Corry, David B.; Su, Shao Bo; Liu, Xialin; Yang, Tianshu

doi:10.1038/s41598-017-06124-z

Cited by 23 publications

(19 citation statements)

References 37 publications

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“…TGF-β is a pivotal regulator both in pathophysiological angiogenesis and tissue remodeling [ 31 – 33 ]. In microvascular endothelial cell lines, TGF-β1 can promote angiogenesis by regulating thrombospondin-4 (TSP-4) [ 34 ], and IL-37 exerts its pro-angiogenic responses through the TGF-β-ALK1 signaling pathway [ 35 ]. A previous study showed that the inhibition of PI3K signaling might be a promising therapeutic target for thrombotic diseases [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Combination of Circulating miRNA-320a/b and D-Dimer Improves Diagnostic Accuracy in Deep Vein Thrombosis Patients

Jiang

Wang

et al. 2018

Med Sci Monit

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BackgroundD-dimer tests have been widely used to rule-out deep venous thrombosis (DVT), but with low specificity. Circulating microRNAs (miRNAs) are novel promising biomarkers in diverse diseases. The purpose of our study was to identify the diagnostic abilities of circulating miRNA-320a/b and to assess their correlation with plasma D-dimer in DVT and post-thrombotic syndrome (PTS) patients.Material/MethodsPlasma samples were taken from 30 DVT patients, 30 PTS patients, and 30 age- and sex-matched healthy volunteers. Quantitative real-time PCR (qPCR) assay and turbidimetric immunoassay were conducted to assess the concentrations of miRNA-320a/b and D-dimer in plasma.ResultsCirculating miRNA-320a and miRNA-320b were significantly upregulated in DVT patients with fold changes of 1.58 and 1.79, respectively. The receiver operating characteristic (ROC) curve analysis showed area under the curve (AUC) values of 0.70 (95% CI: 0.56–0.83) for miRNA-320a and 0.79 (95% CI: 0.67–0.90) for miRNA-320b. Moreover, plasma levels of miRNA-320b were associated with D-dimer values (r=0.52, 95% CI: 0.19–0.74) in DVT. However, no significant changes in plasma miRNA-320a/b and D-dimer were detected in PTS patients.ConclusionsCompared with controls, circulating miRNA-320a/b was differentially expressed in DVT. Simultaneous detection of miRNA-320a/b with D-dimer may improve diagnostic accuracy of DVT.

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Section: Discussionmentioning

confidence: 99%

Combination of Circulating miRNA-320a/b and D-Dimer Improves Diagnostic Accuracy in Deep Vein Thrombosis Patients

Jiang

Wang

et al. 2018

Med Sci Monit

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“…These results demonstrated that the antitumor role of IL‐37 in NSCLC development could be through inhibiting tumor angiogenesis. However, some studies have suggested IL‐37 as a proangiogenic factor, which needs further investigation.…”

Section: Il‐37 In Tumormentioning

confidence: 97%

“…Moreover, this proangiogenic effect was not influenced when IL‐1R8 or IL‐18Rα were neutralized, indicating that other unknown receptors are involved in this process. Two years later, the same research group identified this unknown receptor as ALK1 receptor complex . They found that TGF‐β may act as the bridging molecular that mediates IL‐37 binding to the TGF‐β receptor complex, thus promoting the angiogenesis process.…”

Section: Mechanisms Involved In Il‐37 Antitumor Effects and Future Pementioning

confidence: 99%

IL‐37: An anti‐inflammatory cytokine with antitumor functions

Liu

2018

Cancer Reports

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Background IL‐37 is a newly identified IL‐1 family cytokine. Unlike other members in IL‐1 family, IL‐37 has been demonstrated to be an anti‐inflammatory cytokine in many inflammatory and autoimmune diseases. IL‐37 is regarded as a dual‐function cytokine as both the extracellular and intracellular IL‐37 are biologically functional. Extracellular IL‐37 can bind to IL‐18Rα and IL‐1R8 to form a triple complex, regulating the downstream STAT3 and PTEN signaling. Intracellular IL‐37 can interact with Smad3, translocate into nucleus, and regulate downstream target gene expressions. Recently, the role of IL‐37 in tumor development has been extensively studied. Recent findings IL‐37 has been found to play an antitumor role in various types of tumors, such as non‐small cell lung cancer, hepatocellular carcinoma, and renal cell carcinoma. Many mechanism studies have been carried out to elaborate the possible effects of IL‐37 on tumor growth, immune responses, and tumor angiogenesis. More importantly, the function of IL‐37 may be dependent on its concentration and receptor expression. It can form dimers at high concentrations to be inactivated, thus inhibiting its anti‐inflammatory function. We focused on the role of IL‐37 in various tumor types and provided the hypothesis regarding the underlying mechanisms. Conclusion IL‐37 may affect tumor development through multiple mechanisms: (1) IL‐37 directly influences tumor cell viability; (2) IL‐37 regulates the immune response to promote the antitumor immunity; and (3) IL‐37 suppresses tumor angiogenesis in the tumor microenvironment. Future studies are warranted to further investigate the mechanisms of these multifaceted functions of IL‐37 in animal models and cancer patients.

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“…In vivo study also showed that IL‐37 could promote angiogenesis in pathophysiologic settings 28 . Furthermore, IL‐37 could induce proangiogenesis responses through TGF‐β signaling 29 …”

Section: Introductionmentioning

confidence: 95%

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

Zhu

Teo

et al. 2020

Journal of Leukocyte Biology

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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.

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Interleukin 37 promotes angiogenesis through TGF-β signaling

Cited by 23 publications

References 37 publications

Combination of Circulating miRNA-320a/b and D-Dimer Improves Diagnostic Accuracy in Deep Vein Thrombosis Patients

Combination of Circulating miRNA-320a/b and D-Dimer Improves Diagnostic Accuracy in Deep Vein Thrombosis Patients

IL‐37: An anti‐inflammatory cytokine with antitumor functions

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

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