5-Fluorouracil induces diarrhea with changes in the expression of inflammatory cytokines and aquaporins in mouse intestines

PLoS One. 2013;8(1):e54788. doi: 10.1371/journal.pone.0054788. Epub 2013 Jan 30.


Although the mechanisms of 5-fluorouracil (5-FU)-induced diarrhea remain unclear, accumulating evidence has indicated that changes in the mucosal immune system and aquaporins (AQPs) may play a role in its pathogenesis. Therefore, we investigated the possible changes in the gene expression of inflammatory cytokines and AQPs in the intestines of mice with 5-FU-induced diarrhea. In the present study, the expressions of mRNAs that encode inflammatory cytokines, TNF-α, IL-1β, IL-6, Il-17A and IL-22, were significantly increased throughout the entire colon of mice that exhibited diarrhea following 5-FU administration. In contrast, the gene expression of IFNγ was upregulated only in the distal colon. These increases were significantly reduced by the administration of etanercept. However, 5-FU-induced diarrhea was not recovered by etanercept. On the other hand, the genes for AQPs 4 and 8 were markedly present in the colon, and these expressions in the intestines were significantly decreased by treatment with 5-FU. These decreases were not reversed by etanercept. These findings suggest TNF-α neutralization had no effect on the acutely 5-FU-induced diarrhea and impaired AQPs but reduced dramatically several inflammatory cytokines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / administration & dosage
  • Antimetabolites, Antineoplastic / adverse effects
  • Aquaporins / genetics*
  • Body Weight / drug effects
  • Cytokines / genetics*
  • Cytokines / immunology
  • Diarrhea / chemically induced*
  • Diarrhea / genetics*
  • Diarrhea / immunology
  • Etanercept
  • Fluorouracil / administration & dosage
  • Fluorouracil / adverse effects*
  • Gene Expression Regulation / drug effects
  • Immunoglobulin G / administration & dosage
  • Immunoglobulin G / pharmacology
  • Inflammation Mediators*
  • Intestinal Mucosa / metabolism*
  • Intestines / immunology
  • Male
  • Mice
  • Receptors, Tumor Necrosis Factor / administration & dosage


  • Antimetabolites, Antineoplastic
  • Aquaporins
  • Cytokines
  • Immunoglobulin G
  • Inflammation Mediators
  • Receptors, Tumor Necrosis Factor
  • Etanercept
  • Fluorouracil

Grant support

KAKENHI (24790582) and by a Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science (http://www.jsps.go.jp/j-grantsinaid/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.