Dataset Information

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.

SUBMITTER: Wang J

PROVIDER: S-EPMC4991385 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Wang Juan J Peng Liang L Zhang Ruihua R Zheng Zihan Z Chen Chun C Cheung Ka Lung KL Cui Miao M Bian Guanglin G Xu Feihong F Chiang David D Hu Yuan Y Chen Ye Y Lu Geming G Yang Jianjun J Zhang Hui H Yang Jianfei J Zhu Hongfa H Chen Shu-Hsia SH Liu Kebin K Zhou Ming-Ming MM Sikora Andrew G AG Li Liwu L Jiang Bo B Xiong Huabao H

Oncotarget 20160401 15

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, t ...[more]

PMID: 27027355

Similar Datasets

Project description:Background5-fluorouracil, a commonly used chemotherapeutic agent, up-regulates expression of human thymidylate synthase (hTS). Several different regulatory mechanisms have been proposed to mediate this up-regulation in distinct cell lines, but their specific contributions in a single cell line have not been investigated to date. We have established the relative contributions of these previously proposed regulatory mechanisms in the ovarian cancer cell line 2008 and the corresponding cisplatin-resistant and 5-FU cross-resistant-subline C13*.Methodology/principal findingsUsing RNA polymerase II inhibitor DRB treated cell cultures, we showed that 70-80% of up-regulation of hTS results from transcriptional activation of TYMS mRNA. Moreover, we report that 5-FU compromises the cell cycle by blocking the 2008 and C13* cell lines in the S phase. As previous work has established that TYMS mRNA is synthesized in the S and G(1) phase and hTS is localized in the nuclei during S and G(2)-M phase, the observed cell cycle changes are also expected to affect the intracellular regulation of hTS. Our data also suggest that the inhibition of the catalytic activity of hTS and the up-regulation of the hTS protein level are not causally linked, as the inactivated ternary complex, formed by hTS, deoxyuridine monophosphate and methylenetetrahydrofolate, was detected already 3 hours after 5-FU exposure, whereas substantial increase in global TS levels was detected only after 24 hours.Conclusions/significanceAltogether, our data indicate that constitutive TYMS mRNA transcription, cell cycle-induced hTS regulation and hTS enzyme stability are the three key mechanisms responsible for 5-fluorouracil induced up-regulation of human thymidylate synthase expression in the two ovarian cancer cell lines studied. As these three independent regulatory phenomena occur in a precise order, our work provides a feasible rationale for earlier observed synergistic combinations of 5-FU with other drugs and may suggest novel therapeutic strategies.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets