de Koning Barbara A E, Sluis Maria van der, Lindenbergh-Kortleve Dicky J, Velcich Anna, Pieters Rob, Büller Hans A, Einerhand Alexandra W C, Renes Ingrid B
Division of Pediatric Oncology, Laboratory of Pediatrics, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
J Cell Physiol. 2007 Jan;210(1):144-52. doi: 10.1002/jcp.20822.
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.
黏蛋白Muc2或Mycin2（Muc2）是保护性黏液层的主要结构成分，在化疗诱导的黏膜炎期间已显示其表达上调。由于Muc2已显示具有保护能力，Muc2的上调可能是肠道针对黏膜炎的一种保护反应。因此，提高Muc2蛋白水平可能是预防或减轻黏膜炎的治疗靶点。我们的目的是确定Muc2在化疗诱导的黏膜炎中的作用。通过注射甲氨蝶呤（MTX）在Muc2基因敲除（Muc2(-/-)）和野生型（Muc2(+/+)）小鼠中诱导黏膜炎。在MTX治疗后第2 - 6天对动物称重并处死，分析空肠段。在MTX治疗前，Muc2(+/+)和Muc2(-/-)小鼠的小肠在上皮形态和增殖方面相似。此外，Muc2(+/+)和Muc2(-/-)小鼠之间蔗糖酶 - 异麦芽糖酶和三叶因子 - 3蛋白表达水平相当。在MTX治疗后第3天之前，体重减轻的百分比没有差异。此后，Muc2(+/+)小鼠显示出体重恢复的趋势，而Muc2(-/-)小鼠继续体重减轻。令人惊讶的是，MTX诱导的Muc2(-/-)和Muc2(+/+)小鼠的肠道损伤相当。在注射MTX之前，Muc2(-/-)小鼠中肿瘤坏死因子 - α和白细胞介素 - 10的mRNA上调，可能是由于肠道持续暴露于腔内抗原。Muc2缺乏不会导致化疗诱导的黏膜炎增加。一种可能的解释是，Muc2缺乏可能触发免疫系统在MTX治疗前释放白细胞介素 - 10（一种抗炎细胞因子）的机制。
