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International Immunology Advance Access originally published online on April 24, 2006
International Immunology 2006 18(6):941-949; doi:10.1093/intimm/dxl030
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Contributions of mucosal immune cells to methotrexate-induced mucositis

Barbara AE de Koning1,2,, Jolanda M van Dieren3, Dicky J Lindenbergh-Kortleve2, Maria van der Sluis4, Tetsuya Matsumoto5, Keizo Yamaguchi6, Alexandra W Einerhand2, Janneke N Samsom2, Rob Pieters1 and Edward ES Nieuwenhuis2

1 Division of Pediatric Oncology, Erasmus MC—Sophia Children's Hospital, Dr Molewaterplein 60, PO Box 2060, 3000 GE Rotterdam, the Netherlands
2 Division of Pediatric Gastroenterology, Erasmus MC—Sophia Children's Hospital, Dr Molewaterplein 60, PO Box 2060, 3000 GE Rotterdam, the Netherlands
3 Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
4 Division of Neonatology, Erasmus MC—Sophia Children's Hospital, Rotterdam, the Netherlands
5 Department of Microbiology, Tokyo Medical School, Tokyo, Japan
6 Department of Microbiology, Toho University School of Medicine, Tokyo, Japan

Correspondence to: E. E. S. Nieuwenhuis; E-mail: e.nieuwenhuis{at}erasmusmc.nl

The use of high doses of the anti-cancer drug methotrexate (MTX) is associated with intestinal damage. As a result, mucosal immune cells become increasingly exposed to a vast amount of microbial stimuli. We aimed at determining whether these cells are still functional during MTX treatment. Furthermore, we assessed if activation of the mucosal immune system would play a role in the pathogenesis of mucositis. A contributive role to mucositis for the adaptive immune system was established by showing that mucosal lymphocytes from MTX-treated mice secreted enhanced amounts of cytokines upon ex vivo polyclonal stimulation. Next, in vitro experiments revealed that macrophages were not affected by MTX in the capacity to produce tumor necrosis factor-{alpha} (TNF-{alpha}) and IL-10 after LPS exposure. Moreover, peritoneal macrophages from MTX-treated mice produced more IL-10 and TNF-{alpha} upon LPS stimulation, compared with cells derived from control mice. These data indicate a persistence of both innate and adaptive immune responses in this model. The clinical relevance of these findings was further established by the fact that LPS exposure prior to MTX treatment aggravated the course of mucositis. Furthermore, LPS-responsive mice recovered more slowly compared with LPS-unresponsive mice from MTX treatment. Finally, we found an increase in weight loss and intestinal damage upon MTX treatment in IL-10-deficient mice in comparison to wild-type controls, suggesting a protective role for IL-10 in mucositis. We conclude that mucosal immune responses remain resilient during MTX-induced mucositis. Whereas TNF-{alpha} production may contribute to mucosal damage, IL-10 may regulate by restricting excessive mucositis.

Keywords: innate and adaptive immune system, intestinal damage, LPS, MTX

Transmitting editor: W. Strober


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