Methotrexate-induced mucositis in mucin 2-deficient mice.
The mucin Muc2 or Mycin2 (Muc2), which is the main structural component of the protective mucus layer, has shown to be upregulated during chemotherapy-induced mucositis. As Muc2 has shown to have protective capacities, upregulation of Muc2 may be a counter reaction of the intestine protecting against mucositis. Therefore, increasing Muc2 protein levels could be a therapeutic target in mucositis prevention or reduction. Our aim was to determine the role of Muc2 in chemotherapy-induced mucositis. Mucositis was induced in Muc2 knockout (Muc2(-/-)) and wild type (Muc2(+/+)) mice by injecting methotrexate (MTX). Animals were weighed and sacrificed on Days 2-6 after MTX treatment and jejunal segments were analyzed. Before MTX treatment, the small intestine of Muc2(+/+) and Muc2(-/-) mice were similar with respect to epithelial morphology and proliferation. Moreover, sucrase-isomaltase and trefoil factor-3 protein expression levels were comparable between Muc2(+/+) and Muc2(-/-) mice. Up to Day 3 after MTX treatment, percentages of weight-loss did not differ. Thereafter, Muc2(+/+) mice showed a trend towards regaining weight, whereas Muc2(-/-) mice continued to lose weight. Surprisingly, MTX-induced intestinal damage of Muc2(-/-) and Muc2(+/+) mice was comparable. Prior to MTX-injection, tumor necrosis factor-alpha and interleukin-10 mRNAs were upregulated in Muc2(-/-) mice, probably due to continuous exposure of the intestine to luminal antigens. Muc2 deficiency does not lead to an increase in chemotherapy-induced mucositis. A possible explanation is the mechanism by which Muc2 deficiency may trigger the immune system to release interleukin-10, an anti-inflammatory cytokine before MTX-treatment.
de Koning
Barbara A E
BA
Division of Pediatric Oncology, Laboratory of Pediatrics, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
Sluis
Maria van der
Mv
Lindenbergh-Kortleve
Dicky J
DJ
Velcich
Anna
A
Pieters
Rob
R
Büller
Hans A
HA
Einerhand
Alexandra W C
AW
Renes
Ingrid B
IB
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D049109:Cell Proliferation; D004751:Enteritis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D020895:Enterocytes / Q000378:metabolism; D020397:Goblet Cells / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007410:Intestinal Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007422:Intestines / Q000473:pathology*; D007583:Jejunum / Q000473:pathology; D008727:Methotrexate / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D055262:Mucin-2; D009077:Mucins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D052016:Mucositis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D013394:Sucrase-Isomaltase Complex / Q000378:metabolism; D013997:Time Factors; D000071165:Trefoil Factor-3; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; C524626:Muc2 protein, mouse; D055262:Mucin-2; D009077:Mucins; D012333:RNA, Messenger; C493263:Tff3 protein, mouse; D000071165:Trefoil Factor-3; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D013394:Sucrase-Isomaltase Complex; D008727:Methotrexate