Plenary Lecture

Methotrexate-Induced Intestinal Barrier Dysfunction

Professor Toshiharu Horie
Biopharmaceutics and Molecular Toxicology Unit
Faculty of Pharmaceutical Sciences
Teikyo Heisei University

Abstract: Methotrexate (MTX), a folate antagonist and inhibitor of the dihydrofolate reductase, has been used for the treatment of acute leukemia, rheumatoid arthritis, and intraosseous sarcoma. MTX is known to induce gastrointestinal toxicity such as abdominal pain, diarrhea and nausea. We found production of reactive oxygen species, change of intestinal permeability, change of Zonula Occludens-1 which forms tight junction, and neutrophil infiltration in the small intestine of MTX-treated rats. Intending to investigate the mechanism of MTX-induced intestinal barrier dysfunction, we measured the release of IL-8 (neutrophil chemotactic factor) into cultured medium of T84 (human colonic carcinoma cell) exposed to MTX for 72 hr (conditioned medium). Neutrophil transmigration across T84 monolayer was assessed in a transwell migration study. The results showed that there was significant elevation of IL-8 production and release into cultured medium on exposure to MTX for 72 hr. In the transmigration assay, significant neutrophil migration across the T84 monolayer was observed on the addition of the conditioned medium. This increase of transmigration was inhibited by the addition of neutralizing antibody to IL-8. From these results, MTX-induced release of neutrophil chemotactic factor (IL-8) resulted in the intestinal neutrophil migration which may possibly lead to exacerbation of inflammation.

Brief Biography of the Speaker: Toshiharu Horie graduated from the University of Tokyo, Faculty of Pharmaceutical Sciences in 1972. After he graduated from its Graduate School of Pharmaceutical Sciences, he got a position of an assistant professor in Tokyo University of Pharmacy and Life Sciences, and then, became an associate professor in 1992. He moved to Chiba University, Faculty of Pharmaceutical Sciences as a professor in 1994 and became a professor of Chiba University, Graduate School of Pharmaceutical Sciences in 2001. He became a professor emeritus of Chiba University in 2013 and is a professor of Teikyo Heisei University, Faculty of Pharmaceutical Sciences, from 2013. His research area is biopharmaceutics and drug toxicity.