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It occurs, however, in many disease conditions including cancers. Vascular endothelial growth factor\u2010C\/D (<jats:styled-content style=\"fixed-case\">VEGF<\/jats:styled-content>\u2010C\/D) and <jats:styled-content style=\"fixed-case\">VEGF<\/jats:styled-content> receptor\u20103 (Vegfr3) play a critical role in the regulation of lymphangiogenesis. We investigated how the <jats:styled-content style=\"fixed-case\">VEGF<\/jats:styled-content>\u2010C\/Vegfr3 signalling system is regulated by tumour necrosis factor superfamily member 15 (Tnfsf15), an endothelium\u2010derived cytokine. We report here that Tnfsf15, which is known to induce apoptosis in vascular endothelial cells, can promote lymphatic endothelial cell (<jats:styled-content style=\"fixed-case\">LEC<\/jats:styled-content>) growth and migration, stimulate lymphangiogenesis, and facilitate lymphatic circulation. Treatment of mouse <jats:styled-content style=\"fixed-case\">LECs<\/jats:styled-content> with Tnfsf15 results in up\u2010regulation of Vegfr3 expression; this can be inhibited by gene silencing of death domain\u2010containing receptor\u20103 (<jats:styled-content style=\"fixed-case\">DR3<\/jats:styled-content>; Tnfrsf25), a cell surface receptor for Tnfsf15, with <jats:styled-content style=\"fixed-case\">siRNA<\/jats:styled-content>, or by blocking Tnfsf15\u2013<jats:styled-content style=\"fixed-case\">DR3<\/jats:styled-content> interaction with a Tnfsf15 neutralizing antibody, 4\u2010<jats:styled-content style=\"fixed-case\">3H<\/jats:styled-content>. Additionally, Tnfsf15\/<jats:styled-content style=\"fixed-case\">DR3<\/jats:styled-content> signalling pathways in <jats:styled-content style=\"fixed-case\">LECs<\/jats:styled-content> include activation of <jats:styled-content style=\"fixed-case\">NF\u2010\u03baB<\/jats:styled-content>. Tnfsf15\u2010overexpressing transgenic mice exhibit a marked enhancement of lymph drainage; this is confirmed by treatment of wild\u2010type mice with intraperitoneal injection of recombinant Tnfsf15. Moreover, systemic treatment of pregnant Tnfsf15 transgenic mice with 4\u2010<jats:styled-content style=\"fixed-case\">3H<\/jats:styled-content> leads to inhibition of embryonic lymphangiogenesis. Our data indicate that Tnfsf15, a cytokine produced largely by endothelial cells, facilitates lymphangiogenesis by up\u2010regulating <jats:italic>Vegfr3<\/jats:italic> gene expression in <jats:styled-content style=\"fixed-case\">LECs<\/jats:styled-content>, 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. Copyright \u00a9 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4577","type":"journal-article","created":{"date-parts":[[2015,6,22]],"date-time":"2015-06-22T04:26:32Z","timestamp":1434947192000},"page":"307-318","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Tumour necrosis factor superfamily member 15 (Tnfsf15) facilitates lymphangiogenesis via up\u2010regulation of <i>Vegfr3<\/i> gene expression in lymphatic endothelial cells"],"prefix":"10.1002","volume":"237","author":[{"given":"Ting\u2010Ting","family":"Qin","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research Nankai University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo\u2010Ce","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology 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