title: IL-37 Is a Novel Proangiogenic Factor of Developmental and Pathological Angiogenesis.
abstract: 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.
  
  
  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.
authors.affiliation: From 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.
authors.forename: Tianshu
authors.initials: T
authors.lastname: Yang
authors.affiliation: From 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.).
authors.forename: Qing
authors.initials: Q
authors.lastname: Lin
authors.affiliation: From 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.).
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Zhao
authors.affiliation: From 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.).
authors.forename: Yongguang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: From 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.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.affiliation: From 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.).
authors.forename: Jiayi
authors.initials: J
authors.lastname: Jin
authors.affiliation: From 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.).
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhou
authors.affiliation: From 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.).
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
authors.affiliation: From 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.).
authors.forename: Rongbin
authors.initials: R
authors.lastname: Wei
authors.affiliation: From 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.).
authors.forename: Xuetao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From 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.).
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yang
authors.affiliation: From 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.).
authors.forename: Gaoqin
authors.initials: G
authors.lastname: Liu
authors.affiliation: From 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.).
authors.forename: Peirong
authors.initials: P
authors.lastname: Lu
authors.affiliation: From 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.).
authors.forename: Guotong
authors.initials: G
authors.lastname: Xu
authors.affiliation: From 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.).
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
authors.affiliation: From 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.).
authors.forename: David B
authors.initials: DB
authors.lastname: Corry
authors.affiliation: From 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.).
authors.forename: Shao Bo
authors.initials: SB
authors.lastname: Su
authors.affiliation: From 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.
authors.forename: Shangfeng
authors.initials: S
authors.lastname: Liu
authors.affiliation: From 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.
authors.forename: Xialin
authors.initials: X
authors.lastname: Liu
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D015687:Cell Hypoxia; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015861:Retinal Neovascularization / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D012178:Retinopathy of Prematurity / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014162:Transfection
chemical_list: D043925:Angiogenesis Inducing Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C508587:IL37 protein, human; D007375:Interleukin-1; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: cytokines; endothelial cell; inflammation; interleukins; oxygen-induced retinopathy