TY - JOUR
T1 - Contributions of mucosal immune cells to methotrexate-induced mucositis
AU - de Koning, Barbara A.E.
AU - van Dieren, Jolanda M.
AU - Lindenbergh-Kortleve, Dicky J.
AU - van der Sluis, Maria
AU - Matsumoto, Tetsuya
AU - Yamaguchi, Keizo
AU - Einerhand, Alexandra W.
AU - Samsom, Janneke N.
AU - Pieters, Rob
AU - Nieuwenhuis, Edward E.S.
N1 - Funding Information:
We thank Prof. H. A. Büller for critically reading the manuscript. This work was supported by a grant from Numico Research BV, Wageningen, the Netherlands.
PY - 2006/6
Y1 - 2006/6
N2 - 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-α (TNF-α) and IL-10 after LPS exposure. Moreover, peritoneal macrophages from MTX-treated mice produced more IL-10 and TNF-α 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-α production may contribute to mucosal damage, IL-10 may regulate by restricting excessive mucositis.
AB - 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-α (TNF-α) and IL-10 after LPS exposure. Moreover, peritoneal macrophages from MTX-treated mice produced more IL-10 and TNF-α 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-α production may contribute to mucosal damage, IL-10 may regulate by restricting excessive mucositis.
KW - Innate and adaptive immune system
KW - Intestinal damage
KW - LPS
KW - MTX
UR - http://www.scopus.com/inward/record.url?scp=33745586794&partnerID=8YFLogxK
U2 - 10.1093/intimm/dxl030
DO - 10.1093/intimm/dxl030
M3 - Article
C2 - 16636014
AN - SCOPUS:33745586794
SN - 0953-8178
VL - 18
SP - 941
EP - 949
JO - International Immunology
JF - International Immunology
IS - 6
ER -