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Disruption of the TWEAK/Fn14 pathway prevents 5-fluorouracil-induced diarrhea in mice

World Journal of Gastroenterology 2017年第13期23卷 2294-2307页

作者： Takuhito Sezaki Yuki Hirata Teruki Hagiwara Yuki I Kawamura Tadashi Okamura Rieko Takanashi Kenta Nakano Miwa Tamura-Nakano Linda C Burkly taeko dohi Department of Gastroenterology Research Center for Hepatitis and ImmunologyResearch InstituteNational Center for Global Health and Medicine Research Center for Hepatitis and Immunology Research InstituteNational Center for Global Health and Medicine 2~(nd)Department of Internal Medicine Osaka Medical College Section of Animal Models Department of Infectious DiseasesResearch InstituteNational Center for Global Health and Medicine Communal Laboratory Research InstituteNational Center for Global Health and Medicine Biogen

AIM To clarify the roles of TWEAK and its receptor Fn14 in 5-fluorouracil(5-FU)-induced *** 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 carcinomabearing mice were co-treated with an anti-TWEAK antibody and 5-FU. Embryonic fibroblast response to cytokines was also ***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-17 A, 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-FUinduced intestinal side effects.

关键词： Cancer chemotherapy Interleukin-13 Interleukin-33 Interleukin-13 receptor α2

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