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

作者：Sezaki Takuhito; Hirata Yuki; Hagiwara Teruki; Kawamura Yuki I; Okamura Tadashi; Takanashi Rieko; Nakano Kenta; Tamura Nakano Miwa; Burkly Linda C; Dohi Taeko

来源：World Journal of Gastroenterology, 2017, 23(13): 2294-2307.

DOI：10.3748/wjg.v23.i13.2294

• Cancer chemotherapy
• Interleukin-13
• Interleukin-33
• Interleukin-13 receptor alpha 2

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)alpha 1 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 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-a, and IFN-. in the ileum was Fn14 dependent. The severity of 5-FU-induced diarrhea was lower in IL-13R alpha 1 KO mice, indicating major role for IL-13 signaling via IL13R alpha 1 in pathogenesis. We found that IL-13Ra2, an IL-13 neutralizing/cell protective receptor, was strongly induced by IL-33 in vitro and in vivo. IL-13Ra2 was upregulated in the ileum of 5-FU-treated Fn14 KO mice. Thus, the deletion of Fn14 upregulated IL13Ra2 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-13Ra2, to attenuate 5-FUinduced intestinal side effects.

• 出版日期2017-4-7