title: Tumour necrosis factor superfamily member 15 (Tnfsf15) facilitates lymphangiogenesis via up-regulation of Vegfr3 gene expression in lymphatic endothelial cells.
abstract: Lymphangiogenesis is essential in embryonic development but is rare in adults. It occurs, however, in many disease conditions including cancers. Vascular endothelial growth factor-C/D (VEGF-C/D) and VEGF receptor-3 (Vegfr3) play a critical role in the regulation of lymphangiogenesis. We investigated how the VEGF-C/Vegfr3 signalling system is regulated by tumour necrosis factor superfamily member 15 (Tnfsf15), an endothelium-derived cytokine. We report here that Tnfsf15, which is known to induce apoptosis in vascular endothelial cells, can promote lymphatic endothelial cell (LEC) growth and migration, stimulate lymphangiogenesis, and facilitate lymphatic circulation. Treatment of mouse LECs with Tnfsf15 results in up-regulation of Vegfr3 expression; this can be inhibited by gene silencing of death domain-containing receptor-3 (DR3; Tnfrsf25), a cell surface receptor for Tnfsf15, with siRNA, or by blocking Tnfsf15-DR3 interaction with a Tnfsf15 neutralizing antibody, 4-3H. Additionally, Tnfsf15/DR3 signalling pathways in LECs include activation of NF-κB. Tnfsf15-overexpressing transgenic mice exhibit a marked enhancement of lymph drainage; this is confirmed by treatment of wild-type mice with intraperitoneal injection of recombinant Tnfsf15. Moreover, systemic treatment of pregnant Tnfsf15 transgenic mice with 4-3H leads to inhibition of embryonic lymphangiogenesis. Our data indicate that Tnfsf15, a cytokine produced largely by endothelial cells, facilitates lymphangiogenesis by up-regulating Vegfr3 gene expression in LECs, contributing to the maintenance of the homeostasis of the circulatory system. This finding also suggests that Tnfsf15 may be of potential value as a therapeutic tool for the treatment of lymphoedema.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
authors.forename: Guo-Ce
authors.initials: GC
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.|State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Qi
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
authors.forename: Gui-Li
authors.initials: GL
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
authors.forename: Hai-Lin
authors.initials: HL
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
authors.forename: Li-Xia
authors.initials: LX
authors.lastname: Xu
authors.affiliation: School of Medicine, Nankai University, Tianjin, China.|Collaborative Innovation Center for Biotherapy, Nankai University, West China Hospital, Sichuan University, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.affiliation: Department of Biology, South University of Science and Technology of China, Shenzhen, China.
authors.forename: Guozhi
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Department of Biology, South University of Science and Technology of China, Shenzhen, China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Cao
authors.affiliation: Collaborative Innovation Center for Biotherapy, Nankai University, West China Hospital, Sichuan University, China.|State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.|Collaborative Innovation Center for Biotherapy, Nankai University, West China Hospital, Sichuan University, China.
authors.forename: Qiang-Zhe
authors.initials: QZ
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.|Collaborative Innovation Center for Biotherapy, Nankai University, West China Hospital, Sichuan University, China.
authors.forename: Lu-Yuan
authors.initials: LY
authors.lastname: Li
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008196:Lymph / Q000378:metabolism; D042583:Lymphangiogenesis / Q000187:drug effects; D042601:Lymphatic Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D053219:Receptors, Tumor Necrosis Factor, Member 25; D011994:Recombinant Proteins; C506034:Tnfrsf25 protein, mouse; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: DR3; Tnfsf15; Vegfr3; lymphangiogenesis; lymphatic endothelial cell