Angiogenesis

, Volume 16, Issue 1, pp 29–44 | Cite as

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
Original Paper

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/p57KIP2 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.

Keywords

Lymphangiogenesis Interleukin-8 Prox1 Lymphedema Lymphatic endothelial cells 

Supplementary material

10456_2012_9297_MOESM1_ESM.doc (1.6 mb)
Supplementary material 1 (DOC 1587 kb)

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Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Inho Choi
    • 1
    • 2
    • 5
    • 6
  • Yong Suk Lee
    • 1
    • 2
    • 5
  • Hee Kyoung Chung
    • 1
    • 2
    • 5
  • Dongwon Choi
    • 1
    • 2
    • 5
  • Tatiana Ecoiffier
    • 7
  • Ha Neul Lee
    • 1
    • 2
    • 5
  • Kyu Eui Kim
    • 1
    • 2
    • 5
  • Sunju Lee
    • 1
    • 2
    • 5
  • Eun Kyung Park
    • 1
    • 2
    • 5
  • Yong Sun Maeng
    • 1
    • 2
    • 5
  • Nam Yun Kim
    • 1
    • 2
    • 5
  • Robert D. Ladner
    • 3
    • 5
  • Nicos A. Petasis
    • 5
    • 8
  • Chester J. Koh
    • 9
  • Lu Chen
    • 7
  • Heinz-Josef Lenz
    • 4
    • 5
  • Young-Kwon Hong
    • 1
    • 2
    • 5
  1. 1.Department of Surgery, Norris Comprehensive Cancer CenterUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer CenterUniversity of Southern CaliforniaLos AngelesUSA
  3. 3.Department of PathologyUniversity of Southern CaliforniaLos AngelesUSA
  4. 4.Division of Medical OncologyUniversity of Southern CaliforniaLos AngelesUSA
  5. 5.Norris Comprehensive Cancer Center, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  6. 6.Department of Pharmaceutical EngineeringHoseo UniversityAsan, ChungnamKorea
  7. 7.Center of Eye Disease and Development, Program in Vision Science, and School of OptometryUniversity of CaliforniaBerkeleyUSA
  8. 8.Department of Chemistry, Dornsife College of Letters, Arts & SciencesUniversity of Southern CaliforniaLos AngelesUSA
  9. 9.Division of Pediatric Urology, Children’s Hospital Los Angeles and Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA

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