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Angiogenesis

, Volume 17, Issue 2, pp 407–418 | Cite as

Src contributes to IL6-induced vascular endothelial growth factor-C expression in lymphatic endothelial cells

  • Yu-Han Huang
  • Hung-Yu Yang
  • Ya-Fen Hsu
  • Pei-Ting Chiu
  • George Ou
  • Ming-Jen HsuEmail author
Original Paper

Abstract

Formation of lymphatic capillaries by lymphatic endothelial cells (LECs) occurs both in normal tissues as well as in pathological processes including tumor metastasis. Interleukin-6 (IL-6), a potent pro-inflammatory cytokine, has been shown to be highly elevated in various cancers. IL-6 has also been shown to increase tumor lymphangiogenesis through vascular endothelial growth factor-C (VEGF-C) induction in tumor cells. Although lymphangiogenesis is associated with lymph node metastasis and also resistance to conventional therapy in various cancers, the precise mechanisms of lymphangiogenesis in LECs remain unclear. This study aimed to investigate the signaling cascade involved in IL-6-induced VEGF-C expression in murine LECs (SV-LEC). The VEGF-C mRNA and protein levels were increased in SV-LECs exposed to IL-6. IL-6 time-dependently induced Src phosphorylation and downstream phosphorylation of ERK1/2 and p38MAPK. In contrast, PP2, an inhibitor of Src signaling, abrogated IL-6′s effects on ERK1/2 and p38MAPK phosphorylation. IL-6 exposure also led to increase in VEGF-C promoter-luciferase activity as well as C/EBPβ- and κB-luciferase activities. VEGF-C promoter-, C/EBPβ- and κB-luciferase activities were all suppressed by Src, ERK1/2 or p38MAPK signaling blockades despite presence of IL-6. Finally, C/EBPβ and p65 binding to the VEGF-C promoter region were increased after IL-6 exposure in SV-LECs. Taken together, we report a Src-mediated ERK1/2 and p38MAPK activation resulting in C/EBPβ and p65 binding to the promoter region of VEGF-C, leading to VEGF-C expression in IL-6-exposed SV-LECs.

Keywords

Lymphatic endothelial cells (LECs) Interleukin-6 (IL-6) Vascular endothelial growth factor-C (VEGF-C) Lymphangiogenesis Src 

Notes

Acknowledgments

We would like to thank Dr. Kjetil Tasken for the kind gift of the p/T81 C/EBP-luc reporter construct and Dr. J.S. Alexander (Shreveport, LA, USA) for the kind gift of the mouse LEC line SV-LEC. This work was supported by grant from the National Science Council of Taiwan [NSC98-2320-B-038-007]; Grant [100TMU-WFH-01-4] from the Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan; and Grant [LSH-2012-04] from the Landseed Hospital, Taoyuan, Taiwan.

Conflicts of interest

None.

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Yu-Han Huang
    • 1
  • Hung-Yu Yang
    • 2
  • Ya-Fen Hsu
    • 3
  • Pei-Ting Chiu
    • 1
  • George Ou
    • 4
  • Ming-Jen Hsu
    • 1
    • 4
    Email author
  1. 1.Graduate Institute of Medical Sciences, College of MedicineTaipei Medical UniversityTaipeiTaiwan
  2. 2.Division of CardiologyTaipei Medical University-Wan Fang HospitalTaipeiTaiwan
  3. 3.Division of General Surgery, Department of SurgeryLandseed HospitalTaoyuanTaiwan
  4. 4.Department of Pharmacology, School of Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan

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