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

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 ZhouAndrew G. Sikora, Liwu Li, Bo Jiang, Huabao Xiong

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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 T_H17 and T_H1 cell differentiation without apparent effect on Treg, T_H2, and significantly suppresses thymidylate synthase (TS) expression in T_H17 and T_H1 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 T_H17 and T_H1 cell differentiation without affecting the differentiation of either Treg or T_H2 cells. Finally, low dose 5-FU is effective in ameliorating colitis development by suppressing T_H17 and T_H1 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 T_H17 and T_H1 immune responses.

Original language	English (US)
Pages (from-to)	19312-19326
Number of pages	15
Journal	Oncotarget
Volume	7
Issue number	15
DOIs	https://doi.org/10.18632/oncotarget.8344
State	Published - Apr 12 2016

Keywords

5-FU
Immune response
Immunity
Immunology and Microbiology Section
T17
TS

ASJC Scopus subject areas

Oncology

Access to Document

10.18632/oncotarget.8344

Cite this

Wang, J., Peng, L., Zhang, R., Zheng, Z., Chen, C., Cheung, K. L., Cui, M., Bian, G., Xu, F., Chiang, D., Hu, Y., Chen, Y., Lu, G., Yang, J., Zhang, H., Yang, J., Zhu, H., Chen, S. H., Liu, K., ... Xiong, H. (2016). 5-Fluorouracil targets thymidylate synthase in the selective suppression of T_H17 cell differentiation. Oncotarget, 7(15), 19312-19326. https://doi.org/10.18632/oncotarget.8344

Wang, J, Peng, L, Zhang, R, Zheng, Z, Chen, C, Cheung, KL, Cui, M, Bian, G, Xu, F, Chiang, D, Hu, Y, Chen, Y, Lu, G, Yang, J, Zhang, H, Yang, J, Zhu, H, Chen, SH, Liu, K, Zhou, MM, Sikora, AG, Li, L, Jiang, B & Xiong, H 2016, '5-Fluorouracil targets thymidylate synthase in the selective suppression of T_H17 cell differentiation', Oncotarget, vol. 7, no. 15, pp. 19312-19326. https://doi.org/10.18632/oncotarget.8344

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

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AU - Wang, Juan

AU - Peng, Liang

AU - Zhang, Ruihua

AU - Zheng, Zihan

AU - Chen, Chun

AU - Cheung, Ka Lung

AU - Cui, Miao

AU - Bian, Guanglin

AU - Xu, Feihong

AU - Chiang, David

AU - Hu, Yuan

AU - Chen, Ye

AU - Lu, Geming

AU - Yang, Jianjun

AU - Zhang, Hui

AU - Yang, Jianfei

AU - Zhu, Hongfa

AU - Chen, Shu Hsia

AU - Liu, Kebin

AU - Zhou, Ming Ming

AU - Sikora, Andrew G.

AU - Li, Liwu

AU - Jiang, Bo

AU - Xiong, Huabao

PY - 2016/4/12

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AB - 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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