Decay-accelerating factor deficiency increases susceptibility to dextran sulfate sodium-induced colitis: Role for complement in inflammatory bowel disease
Decay-accelerating factor deficiency increases susceptibility to dextran sulfate sodium-induced colitis: Role for complement in inflammatory bowel disease
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DOI：
10.4049/jimmunol.172.6.3836
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发表时间：
2004-03-15
影响因子：
4.4
通讯作者：
Medof, ME
中科院分区：
文献类型：
--
作者：
Lin, F;Spencer, D;Medof, ME
腐烂加速因子（DAF 或 CD55）在结肠上皮细胞上表达，但其在粘膜中的功能尚不清楚。在人类中，一部分 DAF 缺陷 (Cromer INAB) 患者会患上炎症性肠病 (IBD)。为了评估 DAF 缺乏如何导致肠道炎症，从而在 IBD 发病机制中发挥作用，我们比较了 Daf1 基因靶向小鼠和对照小鼠中葡聚糖硫酸钠诱导的结肠炎的严重程度。在饮用水中摄入 3% 葡聚糖硫酸钠 7 天后，Dqf1(-/-) 小鼠体重明显减轻（-24.7 +/- 7.5% 对比 -14.2% +/- 4.9%），与对照小鼠的软便相比，表现出均匀的血性腹泻，结肠缩短，脾脏变大。远端结肠的组织学检查显示中性粒细胞和单核细胞浸润大量增加，上皮细胞破坏更大，溃疡增加。结肠外植体器官培养物中细胞因子的产生显示 IL-12 和 IL-6 水平增加。改回常规水十四天后，与几乎没有表现出粪便异常的Daf1(+/+)对照相比，所有Daf1(-/-)小鼠继续腹泻。在该时间点（即恢复期结束）进行的器官培养细胞因子测量显示，与对照相比，IL-10（6 倍）、IL-12（4 倍）和 IL-6（2 倍）以及 TNF-α（> 10 倍）水平显着升高。我们的研究结果表明，正如 IL-10(-/-) 小鼠中的 IL-10 和 IL-2(-/-) 小鼠中的 IL-2 所示，DAF 对补体的控制对于调节肠道稳态也很重要，因此其活性可能参与预防 IBD。
Decay-accelerating factor (DAF or CD55) is expressed on colonic epithelial cells but its function in the mucosa is unknown. In humans, a proportion of DAF-deficient (Cromer INAB) patients develop inflammatory bowel disease (IBD). To evaluate how DAF deficiency may contribute to gut inflammation and thus could play a role in IBD pathogenesis, we compared the severity of dextran sulfate sodium-induced colitis in Daf1 gene-targeted and control mice. Seven days after consuming 3% dextran sulfate sodium in their drinking water, Dqf1(-/-) mice suffered markedly greater weight loss (-24.7 +/- 7.5% vs -14.2% +/- 4.9%), exhibited uniformly bloody diarrhea as compared with soft stool in control mice, developed shortened colons, and had larger spleens. Histological examination of distal colons showed massively increased neutrophilic and mononuclear cell infiltration, greater epithelial cell destruction, and increased ulcerations. Cytokine production in organ cultures of colonic explants showed increased levels of IL-12 and IL-6. Fourteen days after switching back to regular water, in contrast to the Daf1(+/+) controls which showed little stool abnormality, all Daf1(-/-) mice continued to have diarrhea. Organ culture cytokine measurements at this time point, i.e., the end of the recovery phase, showed markedly increased levels of IL-10 (6-fold), IL-12 (4-fold), and IL-6 (2-fold), as well as TNF-alpha (>10-fold) compared with the controls. Our findings argue that, as shown for IL-10 in IL-10(-/-) mice and IL-2 in IL-2(-/-) mice, DAF control of complement additionally is important in regulating gut homeostasis and consequently its activity may participate in protecting against IBD.