title: Interleukin-8 reduces post-surgical lymphedema formation by promoting lymphatic vessel regeneration.
abstract: Lymphedema is mainly caused by lymphatic obstruction and manifested as tissue swelling, often in the arms and legs. Lymphedema is one of the most common post-surgical complications in breast cancer patients and presents a painful and disfiguring chronic illness that has few treatment options. Here, we evaluated the therapeutic potential of interleukin (IL)-8 in lymphatic regeneration independent of its pro-inflammatory activity. We found that IL-8 promoted proliferation, tube formation, and migration of lymphatic endothelial cells (LECs) without activating the VEGF signaling. Additionally, IL-8 suppressed the major cell cycle inhibitor CDKN1C/p57(KIP2) by downregulating its positive regulator PROX1, which is known as the master regulator of LEC-differentiation. Animal-based studies such as matrigel plug and cornea micropocket assays demonstrated potent efficacy of IL-8 in activating lymphangiogenesis in vivo. Moreover, we have generated a novel transgenic mouse model (K14-hIL8) that expresses human IL-8 in the skin and then crossed with lymphatic-specific fluorescent (Prox1-GFP) mouse. The resulting double transgenic mice showed that a stable expression of IL-8 could promote embryonic lymphangiogenesis. Moreover, an immunodeficient IL-8-expressing mouse line that was established by crossing K14-hIL8 mice with athymic nude mice displayed an enhanced tumor-associated lymphangiogenesis. Finally, when experimental lymphedema was introduced, K14-hIL8 mice showed an improved amelioration of lymphedema with an increased lymphatic regeneration. Together, we report that IL-8 can activate lymphangiogenesis in vitro and in vivo with a therapeutic efficacy in post-surgical lymphedema.
authors.affiliation: Department of Surgery, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Inho
authors.initials: I
authors.lastname: Choi
authors.forename: Yong Suk
authors.initials: YS
authors.lastname: Lee
authors.forename: Hee Kyoung
authors.initials: HK
authors.lastname: Chung
authors.forename: Dongwon
authors.initials: D
authors.lastname: Choi
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ecoiffier
authors.forename: Ha Neul
authors.initials: HN
authors.lastname: Lee
authors.forename: Kyu Eui
authors.initials: KE
authors.lastname: Kim
authors.forename: Sunju
authors.initials: S
authors.lastname: Lee
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Park
authors.forename: Yong Sun
authors.initials: YS
authors.lastname: Maeng
authors.forename: Nam Yun
authors.initials: NY
authors.lastname: Kim
authors.forename: Robert D
authors.initials: RD
authors.lastname: Ladner
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Petasis
authors.forename: Chester J
authors.initials: CJ
authors.lastname: Koh
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.forename: Young-Kwon
authors.initials: YK
authors.lastname: Hong
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D042583:Lymphangiogenesis / Q000187:drug effects; D042601:Lymphatic Vessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008209:Lymphedema / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011183:Postoperative Complications / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D053700:Receptors, Interleukin-8 / Q000378:metabolism; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D050761:Cyclin-Dependent Kinase Inhibitor p57; D018398:Homeodomain Proteins; D016209:Interleukin-8; D053700:Receptors, Interleukin-8; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D014212:Tretinoin