Disruption of the TWEAK/Fn14 pathway prevents 5-fluorouracil-induced diarrhea in mice
Takuhito Sezaki1, Yuki Hirata1, Teruki Hagiwara1
1Takuhito Sezaki, Teruki Hagiwara, Yuki I Kawamura, Taeko Dohi, Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan.
Aim:
To clarify the roles of TWEAK and its receptor Fn14 in 5-fluorouracil (5-FU)-induced diarrhea.
Methods:
Diarrhea was induced in wild-type (WT), Fn14 knockout (KO), and IL-13 receptor (IL-13R)α1 KO BALB/c mice using a single injection of 5-FU. Histological analysis, cytokine analysis, and flow cytometry was performed on ileal tissues and cells. Murine colon carcinoma-bearing mice were co-treated with an anti-TWEAK antibody and 5-FU. Embryonic fibroblast response to cytokines was also analyzed.
Results:
5-FU induced high Fn14 expression in epithelial cells. The severity of 5-FU-induced diarrhea was lower in Fn14 KO mice compared with WT mice. Administration of anti-TWEAK antibody reduced 5-FU-induced diarrhea without affecting the antitumor effects of 5-FU in vivo. 5-FU-induced expression of IL-13, IL-17A, TNF-α, and IFN-γ in the ileum was Fn14 dependent. The severity of 5-FU-induced diarrhea was lower in IL-13Rα1 KO mice, indicating major role for IL-13 signaling via IL-13Rα1 in pathogenesis. We found that IL-13Rα2, an IL-13 neutralizing/cell protective receptor, was strongly induced by IL-33 in vitro and in vivo. IL-13Rα2 was upregulated in the ileum of 5-FU-treated Fn14 KO mice. Thus, the deletion of Fn14 upregulated IL-13Rα2 expression, which reduced IL-13 expression and activity.
Conclusion:
Disruption of the TWEAK/Fn14 pathway affects several interconnected pathways, including those associated with IL-13, IL-33, and IL-13Rα2, to attenuate 5-FU-induced intestinal side effects.
Insights
Targeting the TWEAK/Fn14 pathway can reduce 5-fluorouracil (5-FU) induced diarrhea by modulating IL-13 signaling. This approach offers a potential strategy to mitigate chemotherapy side effects without compromising anti-tumor efficacy.
Area of Science:
- Gastroenterology
- Oncology
- Immunology
Background:
- 5-fluorouracil (5-FU) is a widely used chemotherapy agent.
- 5-FU often causes severe gastrointestinal side effects, notably diarrhea.
- The molecular mechanisms underlying 5-FU-induced diarrhea are not fully understood.
Purpose of the Study:
- To investigate the role of the TWEAK/Fn14 pathway in 5-FU-induced diarrhea.
- To explore the relationship between Fn14, TWEAK, and cytokine signaling in chemotherapy-induced gut toxicity.
Main Methods:
- Induction of diarrhea in wild-type, Fn14 knockout, and IL-13 receptor alpha1 knockout mice using 5-FU.
- Histological and cytokine analyses of ileal tissues.
- Treatment with anti-TWEAK antibody in a murine colon cancer model.
Main Results:
- 5-FU treatment upregulated Fn14 expression in epithelial cells.
- Fn14 knockout mice exhibited reduced diarrhea severity compared to wild-type mice.
- Anti-TWEAK antibody administration attenuated diarrhea without affecting 5-FU's anti-tumor effects.
- IL-13 signaling via IL-13Rα1 was identified as a key mediator of diarrhea.
- Fn14 deficiency led to increased IL-13Rα2 expression, which suppressed IL-13 activity.
Conclusions:
- The TWEAK/Fn14 pathway plays a significant role in mediating 5-FU-induced intestinal toxicity.
- Modulating the TWEAK/Fn14 pathway, potentially through IL-13Rα2 upregulation, can alleviate 5-FU-induced diarrhea.
- Targeting this pathway presents a promising therapeutic strategy for managing chemotherapy-related side effects.
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