Distinct inflammatory mechanisms mediate early versus late colitis in mice
Distinct inflammatory mechanisms mediate early versus late colitis in mice
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DOI：
10.1053/gast.2002.30308
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发表时间：
2002-01-01
期刊：
影响因子：
29.4
通讯作者：
Levine, AD
中科院分区：
文献类型：
--
作者：
Spencer, DM;Veldman, GM;Levine, AD
背景与目的：炎症性肠病从急性期到慢性期的进展不容易在患者身上评估，也没有动物模型的特征。我们报道了一项纵向研究，调查了实验性结肠炎模型中粘膜免疫反应的变化。方法：检测IL-10基因缺陷小鼠35周后的结肠炎严重程度、体质量、粪便稠度和血含量、血清淀粉样蛋白A和组织学变化。检测炎症肠段固有层单个核细胞产生相应的IL-12、IL-18、干扰素-γ、肿瘤坏死因子α、IL-4和IL-13。在疾病进展的不同时间给予IL-12中和抗体可以评估其治疗潜力。结果：临床表现和肠道炎症描述了结肠炎的早期阶段(10-24周)，以疾病严重程度的进行性增加为特征，随后是晚期(25周)，慢性炎症无限期地持续。早期疾病小鼠的固有层单核细胞逐渐合成更多的IL-12和干扰素伽马，而这两种细胞因子的产生显著下降，并在结肠炎晚期恢复到疾病前的水平。与这种模式一致，IL-12的中和抗体逆转了疾病的早期，但不是晚期。相反，IL-4和IL-13的产生从疾病前期到早期到晚期逐渐增加。结论：IL-10缺陷小鼠的结肠炎发展为两个不同的阶段。IL-12在早期结肠炎中起关键作用，而在晚期疾病中IL-4和IL-13的缺失以及IL-4和IL-13的合成表明，其他免疫机制支持慢性炎症。
Background & Aims: Progression from the acute to chronic phase of inflammatory bowel disease cannot be easily evaluated in patients and has not been characterized in animal models. We report a longitudinal study investigating changes in the mucosal immune response in an experimental model of colitis. Methods: Severity of colitis, body mass, stool consistency and blood content, serum amyloid A, and tissue histology were examined in interleukin (IL)-10-deficient mice over 35 weeks. The corresponding production of IL-12, IL-18, interferon gamma, tumor necrosis factor alpha, IL-4, and IL-13 by lamina propria mononuclear cells in the inflamed intestine was measured. Administration of neutralizing antibody to IL-12 at distinct times during disease progression permitted evaluation of its therapeutic potential. Results: The clinical manifestations and intestinal inflammation delineated an early phase of colitis (10-24 weeks), characterized by a progressive increase in disease severity, followed by a late phase (>25 weeks), in which chronic inflammation persisted indefinitely. Lamina propria mononuclear cells from mice with early disease synthesized progressively greater quantities of IL-12 and interferon gamma, whereas production of both cytokines dramatically declined and returned to pre-disease levels in the late phase of colitis. Consistent with this pattern, neutralizing antibody to IL-12 reversed early, but not late, disease. In contrast, IL-4 and IL-13 production increased progressively from pre- to early to late disease. Conclusions: Colitis that develops in IL-10-deficient mice evolves into 2 distinct phases. IL-12 plays a pivotal role in early colitis, whereas Its absence and the synthesis of IL-4 and IL-13 in late disease indicate that other immune mechanisms sustain chronic inflammation.