TGF-β induces M2-like macrophage polarization via SNAIL-mediated suppression of a pro-inflammatory phenotype
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Fan Zhang1,2, Hongsheng Wang2, Xianfeng Wang3, Guanmin Jiang4, Hao Liu5, Ge Zhang2, Hao Wang2, Rui Fang2, Xianzhang Bu2, Shaohui Cai6, Jun Du2
1Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, PR China
2Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China
3Shijiazhuang City Center for Disease Control and Prevention, Shijiazhuang 050000, PR China
4Department of Clinical Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, PR China
5Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou 510095, PR China
6Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou 510632, PR China
Jun Du, email: [email protected]
Shaohui Cai, email: [email protected]
Keywords: SNAIL, TGF-β, macrophage polarization, tumor-associated macrophage, immunotherapy
Received: September 24, 2015 Accepted: June 29, 2016 Published: July 13, 2016
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.
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