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

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.

• Authors: 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
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 15 Pg. 19312-26 (Apr 12 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27027355 (Publication Type: Journal Article)

Chemical References

• Antimetabolites, Antineoplastic
• Cytokines
• Thymidylate Synthase
• Fluorouracil

Topics

• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Blotting, Western
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Colitis (metabolism, prevention & control)
• Cytokines (genetics, metabolism)
• Dose-Response Relationship, Drug
• Fluorouracil (pharmacology)
• Mice, Inbred C57BL
• Mice, Knockout
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Th1 Cells (drug effects, metabolism)
• Th17 Cells (drug effects, metabolism)
• Thymidylate Synthase (antagonists & inhibitors, genetics, metabolism)