Avian leukosis virus subgroup J induces VEGF expression via NF-κB/PI3K-dependent IL-6 production

// Yanni Gao 1 , Yao Zhang 1 , Yongxiu Yao 2 , Xiaolu Guan 1 , Yongzhen Liu 1 , Xiaole Qi 1 , Yongqiang Wang 1 , Changjun Liu 1 , Yanping Zhang 1 , Honglei Gao 1 , Venugopal Nair 2 , Xiaomei Wang 1 and Yulong Gao 1 1 Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China 2 Avian Viral Diseases programme & UK-China Centre of Excellence on Avian Disease Research, The Pirbright Institute, Ash Road, Pirbright, Surrey, GU24 0NF, UK Correspondence to: Yulong Gao, email: // Keywords : ALV-J, interleukin 6, tumorigenesis, VEGF-A, VEGFR-2, Immunology and Microbiology Section, Immune response, Immunity Received : July 13, 2016 Accepted : November 07, 2016 Published : November 10, 2016 Abstract Avian leukosis virus subgroup J (ALV-J) is an oncogenic virus causing hemangiomas and myeloid tumors in chickens. Interleukin-6 (IL-6) is a multifunctional pro-inflammatory interleukin involved in many types of cancer. We previously demonstrated that IL-6 expression was induced following ALV-J infection in chickens. The aim of this study is to characterize the mechanism by which ALV-J induces IL-6 expression, and the role of IL-6 in tumor development. Our results demonstrate that ALV-J infection increases IL-6 expression in chicken splenocytes, peripheral blood lymphocytes, and vascular endothelial cells. IL-6 production is induced by the ALV-J envelope protein gp85 and capsid protein p27 via PI3K- and NF-κB-mediated signaling. IL-6 in turn induced expression of vascular endothelial growth factor (VEGF)-A and its receptor, VEGFR-2, in vascular endothelial cells and embryonic vascular tissues. Suppression of IL-6 using siRNA inhibited the ALV-J induced VEGF-A and VEGFR-2 expression in vascular endothelial cells, indicating that the ALV-J-induced VEGF-A/VEGFR-2 expression is mediated by IL-6. As VEGF-A and VEGFR-2 are important factors in oncogenesis, our findings suggest that ALV-J hijacks IL-6 to promote tumorigenesis, and indicate that IL-6 could potentially serve as a therapeutic target in ALV-J infections.