Rui Fang

// Fan Zhang 1, 2 , Hongsheng Wang 2 , Xianfeng Wang 3 , Guanmin Jiang 4 , Hao Liu 5 , Ge Zhang 2 , Hao Wang 2 , Rui Fang 2 , Xianzhang Bu 2 , Shaohui Cai 6 , Jun Du 2 1 Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, PR China 2 Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China 3 Shijiazhuang City Center for Disease Control and Prevention, Shijiazhuang 050000, PR China 4 Department of Clinical Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, PR China 5 Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou 510095, PR China 6 Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou 510632, PR China Correspondence to: Jun Du, email: dujun@mail.sysu.edu.cn Shaohui Cai, email: caish5689@sina.com Keywords: SNAIL, TGF-β, macrophage polarization, tumor-associated macrophage, immunotherapy Received: September 24, 2015     Accepted: June 29, 2016     Published: July 13, 2016 ABSTRACT Tumor-associated macrophages (TAMs) are a major component of leukocytic infiltrate in tumors, which facilitates tumor progression and promotes inflammation. TGF-β promotes the differentiation of non-activated macrophages into a TAM-like (M2-like) phenotype; however, the underlying mechanisms are not clear. In this study, we found that TGF-β induces a M2-like phenotype characterized by up-regulation of the anti-inflammatory cytokine IL-10, and down-regulation of the pro-inflammatory cytokines TNF-α and IL-12. In human THP-1 macrophages, overexpression of SNAIL caused M2-like differentiation by inhibiting pro-inflammatory cytokine release and promoting the expression of M2-specific markers. By contrast, SNAIL knockdown promoted M1 polarization through up-regulation of pro-inflammatory cytokines and abolished TGF-β-mediated M2-polarization of THP-1 macrophages. The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-β-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-β skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-β/SNAIL signaling restores the production of pro-inflammatory cytokines. This study provides new understanding of the role of SNAIL in M2 polarization of macrophages, and suggests a potential therapeutic target for antitumor immunity.