Interleukin-8 reduces post-surgical lymphedema formation by promoting lymphatic vessel regeneration

Inho Choi, Yong Suk Lee, Hee Kyoung Chung, Dongwon Choi, Tatiana Ecoiffier, Ha Neul Lee, Kyu Eui Kim, Sunju Lee, Eun Kyung Park, Yong Sun Maeng, Nam Yun Kim, Robert D Ladner, Nicos A Petasis, Chester J Koh, Lu Chen, Heinz-Josef Lenz, Young-Kwon Hong

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)29-44
Number of pages16
JournalAngiogenesis
Volume16
Issue number1
DOIs
Publication statusPublished - Jan 2013

Keywords

  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p57
  • Down-Regulation
  • Embryonic Development
  • Endothelial Cells
  • Homeodomain Proteins
  • Humans
  • Interleukin-8
  • Lymphangiogenesis
  • Lymphatic Vessels
  • Lymphedema
  • Mice
  • Mice, Transgenic
  • Neovascularization, Physiologic
  • Postoperative Complications
  • Receptors, Interleukin-8
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B
  • Regeneration
  • Tretinoin
  • Tumor Microenvironment
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Fingerprint Dive into the research topics of 'Interleukin-8 reduces post-surgical lymphedema formation by promoting lymphatic vessel regeneration'. Together they form a unique fingerprint.

Cite this