5-Fluorouracil targets thymidylate synthase in the selective suppression of  T H 17 cell differentiation

Juan Wang; Liang Peng; Ruihua Zhang; Zihan Zheng; Chun Chen; Ka Lung Cheung; Miao Cui; Guanglin Bian; Feihong Xu; David Chiang; Yuan Hu; Ye Chen; Geming Lu; Jianjun Yang; Hui Zhang; Jianfei Yang; Hongfa Zhu; Shu-hsia Chen; Kebin Liu; Ming-Ming Zhou; Andrew G. Sikora; Liwu Li; Bo Jiang; Huabao Xiong

doi:10.18632/oncotarget.8344

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Research Papers: Immunology:

5-Fluorouracil targets thymidylate synthase in the selective suppression of T_H17 cell differentiation

Juan Wang, Liang Peng, Ruihua Zhang, Zihan Zheng, Chun Chen, Ka Lung Cheung, Miao Cui, Guanglin Bian, Feihong Xu, David Chiang, Yuan Hu, Ye Chen, Geming Lu, Jianjun Yang, Hui Zhang, Jianfei Yang, Hongfa Zhu, Shu-hsia Chen, Kebin Liu, Ming-Ming Zhou, Andrew G. Sikora, Liwu Li, Bo Jiang and Huabao Xiong _

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Oncotarget. 2016; 7:19312-19326. https://doi.org/10.18632/oncotarget.8344

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Abstract

Juan Wang1,2, Liang Peng2, Ruihua Zhang2, Zihan Zheng2,3, Chun Chen4,5, Ka Lung Cheung6, Miao Cui7, Guanglin Bian2, Feihong Xu2, David Chiang2, Yuan Hu2, Ye Chen1, Geming Lu2, Jianjun Yang2, Hui Zhang2, Jianfei Yang8, Hongfa Zhu7, Shu-hsia Chen2, Kebin Liu9, Ming-Ming Zhou6, Andrew G. Sikora2, Liwu Li5, Bo Jiang1 and Huabao Xiong2

1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China

2 Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

3 Department of Biology, College of Arts and Sciences, University of North Carolina at Chapel Hill, NC, USA

4 Amgen Inc., Thousand Oaks, CA, USA

5 Department of Biological Sciences, Virginia Tech, Blacksburg, VA, USA

6 Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

7 Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

8 Tempero Pharmaceuticals, GlasxoSmithKline, Cambridge, MA, USA

9 Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA

Correspondence to:

Huabao Xiong, email:

Bo Jiang, email:

Keywords: 5-FU, TH17, TS, Immunology and Microbiology Section, Immune response, Immunity

Received: November 24, 2015 Accepted: March 07, 2016 Published: March 24, 2016

Abstract

While it is well established that treatment of cancer patients with 5-Fluorouracil (5-FU) can result in immune suppression, the exact function of 5-FU in the modulation of immune cells has not been fully established. We found that low dose 5-FU selectively suppresses TH17 and TH1 cell differentiation without apparent effect on Treg, TH2, and significantly suppresses thymidylate synthase (TS) expression in TH17 and TH1 cells but has a lesser effect in tumor cells and macrophages. Interestingly, the basal expression of TS varies significantly between T helper phenotypes and knockdown of TS significantly impairs TH17 and TH1 cell differentiation without affecting the differentiation of either Treg or TH2 cells. Finally, low dose 5-FU is effective in ameliorating colitis development by suppressing TH17 and TH1 cell development in a T cell transfer colitis model. Taken together, the results highlight the importance of the anti-inflammatory functions of low dose 5-FU by selectively suppressing TH17 and TH1 immune responses.

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Research Papers: Immunology:

5-Fluorouracil targets thymidylate synthase in the selective suppression of TH17 cell differentiation

Abstract

5-Fluorouracil targets thymidylate synthase in the selective suppression of T_H17 cell differentiation