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IL-37 Is a Novel Proangiogenic Factor of Developmental and Pathological Angiogenesis
Tianshu Yang1, Qing Lin2, Mengmeng Zhao2
1From the Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China (T.Y., Q.L., M.Z., Y.H., R.W., X.Z., G.X., J.Y., S.B.S.); Johns Hopkins University School of Medicine, Baltimore, MD (Q.L., X.Y.); State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China (Y.Y., J.J., H.Z., X.H., S.B.S., X.L.); Department of Ophthalmology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China (G.L., P.L.); Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX (D.B.C.); and Department of Stomatology, Huashan Hospital, Fudan University, Shanghai, China (S.L.). tianshuy@tongji.edu.cn shangfengliufudan@163.com liuxl28@mail.sysu.edu.cn.
Objective:
Angiogenesis is tightly controlled by growth factors and cytokines in pathophysiological settings. Interleukin 37 (IL-37) is a newly identified cytokine of the IL-1 family, some members of which are important in inflammation and angiogenesis. However, the function of IL-37 in angiogenesis remains unknown. We aimed to explore the regulatory role of IL-37 in pathological and physiological angiogenesis.
Approach And Results:
We found that IL-37 was expressed and secreted in endothelial cells and upregulated under hypoxic conditions. IL-37 enhanced endothelial cell proliferation, capillary formation, migration, and vessel sprouting from aortic rings with potency comparable with that of vascular endothelial growth factor. IL-37 activates survival signals including extracellular signal-regulated kinase 1/2 and AKT in endothelial cells. IL-37 promoted vessel growth in implanted Matrigel plug in vivo in a dose-dependent manner with potency comparable with that of basic fibroblast growth factor. In the mouse model of retinal vascular development, neonatal mice administrated with IL-37 displayed increased neovascularization. We demonstrated further that IL-37 promoted pathological angiogenesis in the mouse model of oxygen-induced retinopathy.
Conclusions:
Our findings suggest that IL-37 is a novel and potent proangiogenic cytokine with essential role in pathophy siological settings.
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