IL-35 induces N2 phenotype of neutrophils to promote tumor growth

Abstract

// Jiu-Ming Zou 1, * , Jian Qin 1, * , Yong-Chao Li 1 , Yu Wang 1 , Dong Li 1 , Yu Shu 1 , Chao Luo 1 , Shan-Shan Wang 1 , Gang Chi 1 , Fang Guo 1 , Gui-Mei Zhang 1 , Zuo-Hua Feng 1 1 Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, The People’s Republic of China * These authors have contributed equally to this work Correspondence to: Zuo-Hua Feng, email: fengzhg_tj@163.com Yong-Chao Li, email: yongchaolee@outlook.com Keywords: IL-35, neutrophils, inflammation, tumor, cytokine Received: December 08, 2016      Accepted: March 24, 2017      Published: April 04, 2017 ABSTRACT IL-35 is an immunosuppressive cytokine and exerts regulatory effects on T cells, B cells, macrophages and dendritic cells. Neutrophils are important innate immune cells that play key roles in tumor development. The effect of IL-35 on neutrophils remains unknown. Here, we report that IL-35 can induce N2 neutrophil polarization (protumor phenotype) by increasing G-CSF and IL-6 production, and promote neutrophil infiltration into tumor microenvironment. The sustained expression of IL-35 could promote chronic inflammation to augment the proangiogenic and immunosuppressive function of neutrophils. IL-35 stimulated macrophages to secrete proinflammatory cytokines IL-1β and IL-6. IL-1β stimulated γδ T cells to produce IL-17, which in turn increased the production of G-CSF. By increasing the expression of G-CSF and IL-6, IL-35 could up-regulate the expression of MMP-9 and Bv8, and down-regulate TRAIL expression in neutrophils, thus augmenting the proangiogenic function of neutrophils. Moreover, G-CSF/IL-6 induced the enhanced activation of STAT3 and ERK pathways in neutrophils, thus increasing the expression of iNOS to suppress T cell activation. Our findings suggest that IL-35 can promote tumor progression by functioning as an up-stream cytokine to promote cancer-associated inflammation and control neutrophil polarization. Targeting IL-35 might be an important approach for designing new strategy of tumor therapy.