Abstract
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.
Highlights
The antimetabolite agent 5-fluorouracil (5-FU) is most commonly used as a chemotherapy drug in the treatment of various cancers, including colorectal and breast cancers [1]
To investigate whether the development of 5-FU-induced diarrhea is associated with an altered gene expression of inflammatory cytokines in the intestines, we examined the changes in the gene expressions of TNF-a, IL-1b, IL-6, IFNc, IL-17A and IL-22 in the small and large intestines of C57BL/6J mice with 5FU-induced diarrhea
We found that the expression of mRNAs encoding TNF-a, IL-1b, IL-6 IL-17A and IL-22 was dramatically increased in the proximal, transverse and distal colons of mice that exhibited severe diarrhea following the administration of 5-FU
Summary
The antimetabolite agent 5-fluorouracil (5-FU) is most commonly used as a chemotherapy drug in the treatment of various cancers, including colorectal and breast cancers [1]. Gastrointestinal (GI) mucositis is a common side effect of cancer chemotherapy for which there is no efficient treatment. It is currently the most significant dose-limiting toxicity of 5-FU treatment [2]. Cancer chemotherapy-induced intestinal mucositis increases the expression of proinflammatory-cytokines, such as TNF-a, IL-1b, and IL-6 [4,5]. The recirculation of fluids in the GI tract is especially high during a meal, when water is secreted in the upper GI tract to allow the rapid osmotic balancing of intestinal contents, but is continuously absorbed together with nutrients [6]. The absorption of water is one of the key functions of the intestines. It has been reported that a defect in the expression and/or function of AQPs underlies renal diabetes insipidus [22], brain edema [9,23], dry eye [24] and food allergyinduced diarrhea [25]
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