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.
Highlights
Interleukin (IL)-17 producing T helper cells (TH17), are a T helper subtype clearly distinct from T-helper type 1 (TH1), T-helper type 2 (TH2), and T regulatory (Treg) cells, which play an important role in the pathogenesis of various inflammatory and autoimmune diseases [1, 2]
Transforming growth factor β (TGF-β) and Interleukin-6 (IL-6) have been described as key factors contributing to generating de novo TH17 cells [3,4,5], but other cytokines have been shown to have significant auxillary functions as well: IL-23 is necessary for TH17 lineage expansion [2, 6], and IL-21 is involved the differentiation of TH17 cells [7,8,9]
We found that low dose 5-FU selectively suppresses TH17 and TH1 cell differentiation without major effect on Treg, TH2, TH9, TH22 cells, suggesting high and low dose 5-FU may have different effects on immune responses
Summary
Interleukin (IL)-17 producing T helper cells (TH17), are a T helper subtype clearly distinct from T-helper type 1 (TH1), T-helper type 2 (TH2), and T regulatory (Treg) cells, which play an important role in the pathogenesis of various inflammatory and autoimmune diseases [1, 2]. (IL-6) have been described as key factors contributing to generating de novo TH17 cells [3,4,5], but other cytokines have been shown to have significant auxillary functions as well: IL-23 is necessary for TH17 lineage expansion [2, 6], and IL-21 is involved the differentiation of TH17 cells [7,8,9]. The retinoic acid receptor-related orphan nuclear receptor (RORγt) has been identified as a critical transcription factor for TH17 cell differentiation [14] while several other transcription factors including RORα, STAT3, and IRF4 have been reported to be involved [1, 14,15,16]. The NFAT5 pathway has been shown to upregulate TH17cells in response to high salt [19], and the deprivation of free amino acids has been reported to bias against TH17 differentiation [20]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
