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 language | English |
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Pages (from-to) | 29-44 |
Number of pages | 16 |
Journal | Angiogenesis |
Volume | 16 |
Issue number | 1 |
DOIs | |
Publication status | Published - 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