| First Author | Sezaki T | Year | 2017 |
| Journal | World J Gastroenterol | Volume | 23 |
| Issue | 13 | Pages | 2294-2307 |
| PubMed ID | 28428709 | Mgi Jnum | J:253420 |
| Mgi Id | MGI:6109206 | Doi | 10.3748/wjg.v23.i13.2294 |
| Citation | Sezaki T, et al. (2017) Disruption of the TWEAK/Fn14 pathway prevents 5-fluorouracil-induced diarrhea in mice. World J Gastroenterol 23(13):2294-2307 |
| abstractText | 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)alpha1 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-alpha, and IFN-gamma in the ileum was Fn14 dependent. The severity of 5-FU-induced diarrhea was lower in IL-13Ralpha1 KO mice, indicating major role for IL-13 signaling via IL-13Ralpha1 in pathogenesis. We found that IL-13Ralpha2, an IL-13 neutralizing/cell protective receptor, was strongly induced by IL-33 in vitro and in vivo. IL-13Ralpha2 was upregulated in the ileum of 5-FU-treated Fn14 KO mice. Thus, the deletion of Fn14 upregulated IL-13Ralpha2 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-13Ralpha2, to attenuate 5-FU-induced intestinal side effects. |
