Abstract
Background: Glucagon-like peptide-2 (GLP-2) is a pleiotropic hormone secreted from intestinal L-cells. GLP-2 is known to improve and maintain intestinal homeostasis, and shows therapeutic efficacy in small and large bowel inflammation. To clarify the relationship between intestinal GLP-2 dynamics and chemotherapy-induced intestinal injury, we investigated the GLP-2 dynamics in rat small intestine after administration of either methotrexate or 5-fluorouracil.
Methods: Rat were i.p. injected with either methotrexate (50 mg/kg) or 5-fluorouracil (100 mg/kg). At an appropriate time after the injection, the intestinal tissues were dissected out and frozen rapidly in liquid nitrogen and stored until further analysis. Myeloperoxidase and GLP-2 expression and localization were analyzed by immunohistochmical analysis. mRNA expression was analyzed by RT-qPCR.
Results: A single administration of 5-fluorouracil caused intestinal damage in a time-dependent manner up to 72 hrs, whereas methotrexate had almost no effect. At 24 hrs after administration, methotrexate significantly increased mRNA expressions of proglucagon, a precursor of GLP-2, GLP-2 receptor and insulin-like growth factor-1, an essential factor of the intestinal tropic effects of GLP-2. Numbers of anti-GLP-2 antibody positive cells in the intestine were also increased by methotrexate administration. On the other hand, 5-fluorouracil significantly reduced these mRNA expressions as well as the numbers of anti-GLP-2 antibody positive cells. Methotrexate and 5-fluorouracil slightly and significantly increased mRNA expression of dipeptidyl peptidase-4 which inactivates GLP-2, respectively.
Conclusion: Methotrexate accelerated intestinal GLP-2 dynamics without obvious intestinal injury, whereas 5-fluorouracil inhibited the dynamics with serious injury. These results suggest that the effect of anti-cancer drugs on intestinal GLP-2 dynamics is closely correlates with chemotherapy-induced intestinal injury. Methotrexate-induced upregulation of intestinal GLP-2 dynamics may contribute to counteract the intestinal damage by methotrexate.
