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Interleukin-8 reduces post-surgical lymphedema formation by promoting lymphatic vessel regeneration |
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| Authors: | 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 |
| Affiliation: | 1. Department of Surgery, Norris Comprehensive Cancer Center, University of Southern California, 1450 Biggy St. NRT6501, Mail Code 9601, Los Angeles, CA, 90033, USA 2. Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, 1450 Biggy St. NRT6501, Mail Code 9601, Los Angeles, CA, 90033, USA 5. Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 6. Department of Pharmaceutical Engineering, Hoseo University, Asan, Chungnam, Korea 7. Center of Eye Disease and Development, Program in Vision Science, and School of Optometry, University of California, Berkeley, CA, USA 3. Department of Pathology, University of Southern California, Los Angeles, CA, USA 8. Department of Chemistry, Dornsife College of Letters, Arts & Sciences, University of Southern California, Los Angeles, CA, USA 9. Division of Pediatric Urology, Children??s Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 4. Division of Medical Oncology, University of Southern California, Los Angeles, CA, USA |
| 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. |
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