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Published on: November 15, 2024
5-Fluorouracil targets thymidylate synthase in the selective suppression of TH17 cell differentiation
Juan Wang1,2, Liang Peng2, Ruihua Zhang2
1Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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.
Insights
Low dose 5-Fluorouracil (5-FU) selectively suppresses TH17 and TH1 immune responses by targeting thymidylate synthase (TS). This finding reveals 5-FU
Area of Science:
- Immunology
- Pharmacology
- Cancer Biology
Background:
- 5-Fluorouracil (5-FU) is a chemotherapy agent known to cause immune suppression in cancer patients.
- The precise mechanisms by which 5-FU modulates immune cell function remain incompletely understood.
Purpose of the Study:
- To elucidate the specific effects of low-dose 5-FU on immune cell differentiation and function.
- To investigate the role of thymidylate synthase (TS) in 5-FU-mediated immune modulation.
Main Methods:
- Treatment of immune cells with low-dose 5-FU.
- Analysis of T helper cell differentiation (TH17, TH1, Treg, TH2).
- Assessment of thymidylate synthase (TS) expression and function.
- Utilizing a T cell transfer colitis model to evaluate in vivo efficacy.
Main Results:
- Low-dose 5-FU selectively suppressed TH17 and TH1 cell differentiation, with minimal impact on Treg and TH2 cells.
- 5-FU significantly reduced thymidylate synthase (TS) expression in TH17 and TH1 cells, more so than in tumor cells or macrophages.
- TS knockdown impaired TH17 and TH1 differentiation, confirming its role in these T helper cell subsets.
- Low-dose 5-FU ameliorated colitis in a mouse model by suppressing TH17 and TH1 cell development.
Conclusions:
- Low-dose 5-FU exhibits significant anti-inflammatory properties by selectively targeting TH17 and TH1 immune responses.
- The suppression of thymidylate synthase (TS) is a key mechanism underlying 5-FU's selective immunomodulatory effects.
- These findings suggest potential therapeutic applications for low-dose 5-FU in inflammatory conditions.
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