Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 7, 2017; 23(13): 2294-2307
Published online Apr 7, 2017. doi: 10.3748/wjg.v23.i13.2294
Disruption of the TWEAK/Fn14 pathway prevents 5-fluorouracil-induced diarrhea in mice
Takuhito Sezaki, Yuki Hirata, Teruki Hagiwara, Yuki I Kawamura, Tadashi Okamura, Rieko Takanashi, Kenta Nakano, Miwa Tamura-Nakano, Linda C Burkly, Taeko Dohi
Takuhito 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
Yuki Hirata, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan
Yuki Hirata, 2nd Department of Internal Medicine, Osaka Medical College, Osaka 569-8686, Japan
Tadashi Okamura, Rieko Takanashi, Kenta Nakano, Section of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
Miwa Tamura-Nakano, Communal Laboratory, Research Institute, National Center for Global Health and Medicine, Tokyo 162-0855, Japan
Linda C Burkly, Biogen, Cambridge, MA 02142, United States
Author contributions: Sezaki T the majority of experiments, including acquisition of data, study concept and design, analysis and interpretation of data, and drafting the manuscript; Hirata Y, Hagiwara T, Okamura T, Takanashi R, Nakano K and Tamura-Nakano M acquisition of data; Kawamura YI acquisition of data, analysis and interpretation of data, and obtained funding; Burkly LC study concept and design, analysis and interpretation of data, and drafting the manuscript; Dohi T acquisition of data, study concept and design, analysis and interpretation of data, drafting the manuscript, and obtained funding.
Supported by the Grants-in-Aid for Scientific Research, No. [B]5H04503 and No. [C]25460965, No. 16K09299 from the Ministry of Education, Culture, Sports, Science, and Technology; the National Center for Global Health and Medicine, No. 23-101, No. 25-104, No. 26-110, No. 26-117, and No. 27-1406; and the MEXT-Supported Program for the Strategic Research Foundation at Private Universities for Waseda University.
Institutional review board statement: This study was reviewed and approved by the Institutional Review Board of Research Institute, National Center for Global Health and Medicine, Japan.
Institutional animal care and use committee statement: All experimental protocols were approved by the institutional animal care and use committee of the National Center for Global Health and Medicine, Japan (#16086).
Conflict-of-interest statement: Sezaki T, Hirata Y, Hagiwara T, Kawamura YI, Okamura T, Takanashi R, Nakano K, Tamura-Nakano M and Dohi T have no conflicts of interest to disclose. Burkly LC is an employee and stockholder of Biogen
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Taeko Dohi, Director, Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan. dohi@ri.ncgm.go.jp
Telephone: +81-4-73754754 Fax: +81-4-73754766
Received: November 28, 2016
Peer-review started: November 29, 2016
First decision: January 10, 2017
Revised: February 6, 2017
Accepted: March 2, 2017
Article in press: March 2, 2017
Published online: April 7, 2017
Processing time: 129 Days and 9.4 Hours
Abstract
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.

Keywords: Cancer chemotherapy; Interleukin-13; Interleukin-33; Interleukin-13 receptor α2

Core tip: IL-13 signaling via IL-13 receptor (IL-13R)α1 plays a central role in developing diarrhea, a major side effect of 5-fluorouracil (5-FU). Disruption of the TWEAK/Fn14 pathway alleviated diarrhea by downregulating expression of IL-13 and upregulating expression of IL-13Rα2, a decoy IL-13 receptor. The IL-13Rα2 was induced by IL-33 in mesenchymal cells of 5-FU-treated intestines in vivo and fibroblasts in vitro. IL-33 expression was independent of TWEAK/Fn14 signaling, and its cell protective function in 5-FU-treated mice was enhanced in the absence of Fn14. Disruption of the TWEAK/Fn14 pathway affects several interconnected pathways to attenuate 5-FU-induced intestinal side effects.