title: 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.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.|Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Biology, College of Arts and Sciences, University of North Carolina at Chapel Hill, NC, USA.
authors.forename: Zihan
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.|Department of Biological Sciences, Virginia Tech, Blacksburg, VA, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Ka Lung
authors.initials: KL
authors.lastname: Cheung
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: Cui
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Guanglin
authors.initials: G
authors.lastname: Bian
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Feihong
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: Chiang
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Geming
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Tempero Pharmaceuticals, GlasxoSmithKline, Cambridge, MA, USA.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Hongfa
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Shu-Hsia
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.
authors.forename: Kebin
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Sikora
authors.affiliation: Department of Biological Sciences, Virginia Tech, Blacksburg, VA, USA.
authors.forename: Liwu
authors.initials: L
authors.lastname: Li
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D003092:Colitis / Q000378:metabolism / Q000517:prevention & control; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects* / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D016207:Cytokines; D013940:Thymidylate Synthase; D005472:Fluorouracil
keywords: 5-FU; Immune response; Immunity; Immunology and Microbiology Section; TH17; TS