title: Th2 cytokines inhibit lymphangiogenesis.
abstract: Lymphangiogenesis is the process by which new lymphatic vessels grow in response to pathologic stimuli such as wound healing, inflammation, and tumor metastasis. It is well-recognized that growth factors and cytokines regulate lymphangiogenesis by promoting or inhibiting lymphatic endothelial cell (LEC) proliferation, migration and differentiation. Our group has shown that the expression of T-helper 2 (Th2) cytokines is markedly increased in lymphedema, and that these cytokines inhibit lymphatic function by increasing fibrosis and promoting changes in the extracellular matrix. However, while the evidence supporting a role for T cells and Th2 cytokines as negative regulators of lymphatic function is clear, the direct effects of Th2 cytokines on isolated LECs remains poorly understood. Using in vitro and in vivo studies, we show that physiologic doses of interleukin-4 (IL-4) and interleukin-13 (IL-13) have profound anti-lymphangiogenic effects and potently impair LEC survival, proliferation, migration, and tubule formation. Inhibition of these cytokines with targeted monoclonal antibodies in the cornea suture model specifically increases inflammatory lymphangiogenesis without concomitant changes in angiogenesis. These findings suggest that manipulation of anti-lymphangiogenic pathways may represent a novel and potent means of improving lymphangiogenesis.
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Ira L
authors.initials: IL
authors.lastname: Savetsky
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Swapna
authors.initials: S
authors.lastname: Ghanta
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Gardenier
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Torrisi
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Gabriela D
authors.initials: GD
authors.lastname: García Nores
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Geoffrey E
authors.initials: GE
authors.lastname: Hespe
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Nitti
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Raghu P
authors.initials: RP
authors.lastname: Kataru
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Babak J
authors.initials: BJ
authors.lastname: Mehrara
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology*; D018793:Interleukin-13 / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology*; D042583:Lymphangiogenesis / Q000276:immunology*; D008297:Male; D051379:Mice; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D018793:Interleukin-13; D015847:Interleukin-4