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Cancer Chemother Pharmacol (2013) 72:757765
DOI 10.1007/s00280-013-2238-2
ORIGINAL ARTICLE
Disruption of ZO1/claudin4 interaction in relation to inammatory responses in methotrexateinduced intestinal mucositis
Kazuma Hamada Naoko Kakigawa Shuichi Sekine Yoshihisa Shitara Toshiharu Horie
Received: 19 November 2012 / Accepted: 18 July 2013 / Published online: 21 August 2013 Springer-Verlag Berlin Heidelberg 2013
Results MTX increased the mRNA levels of TNF-, IL-1, MIP-2, and TLR4 in the small intestine, as well as the protein expression of claudin-2. Increased claudin-2 and decreased claudin-4 immunostaining were also observed. Occludin mRNA levels were signicantly diminished by MTX administration, whereas occludin protein levels and the interaction between ZO-1 and occludin were unaltered; however, the interaction between ZO-1 and claudin-4 was signicantly compromised.
Conclusions These results indicate that elevated levels of inammatory cytokines and chemokines in the small intestine of MTX-treated rats may contribute to the inhibition of ZO-1/claudin-4 binding, and that inhibition of ZO-1/claudin-4 binding may in turn lead to a reduction in claudin-4 expression.
Keywords Cytokine Methotrexate Mucositis Tight junction ZO-1
Introduction
Gastrointestinal mucositis, or intestinal barrier disruption, is one of the most common side effects in patients undergoing chemotherapy. The variations in clinical severity or progression among patients with mucositis suggest that multiple biological factors contribute to its development, and also that understanding of its exact mechanisms is needed to establish the effective prevention or treatment strategies. Soniss ve-phase model, a widely used mucositis model developed by animal and clinical data, explains that increased cytokine-mediated inammatory responses initiated after the activation of transcriptional factors as well as production of reactive oxygen species (ROS) are a major pathological process that leads to mucositis [1]. However, the molecular
Abstract
Purpose Methotrexate (MTX)-induced intestinal mucositis limits the use of the drug. We previously reported that MTX-dependent production of reactive oxygen species is an initiating signal leading to neutrophil migration and intestinal barrier dysfunction. Moreover, alterations of zonula occludens (ZO)-1, an integral component of tight junctions (TJs), contribute to its dysfunction. This study aimed to clarify the identity of inammatory mediators in the intestine of MTX-treated rats and to evaluate MTX-stimulated alterations in the expression of TJ proteins other than ZO-1 (e.g., occludin and claudins).
Methods Male Wistar rats were administrated MTX (15 mg kg1) orally once daily for 4 days. Tumor necrosis...