Down-regulation of intestinal lymphocyte activation and Th1 cytokine production by antibiotic therapy in a murine model of Crohn's disease
Down-regulation of intestinal lymphocyte activation and Th1 cytokine production by antibiotic therapy in a murine model of Crohn's disease
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DOI：
10.4049/jimmunol.169.9.5308
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发表时间：
2002-11-01
影响因子：
4.4
通讯作者：
Cominelli, F
中科院分区：
文献类型：
--
作者：
Bamias, G;Marini, M;Cominelli, F
肠道常驻细菌可能通过与肠道免疫系统的相互作用在克罗恩病的发病机制中发挥重要作用。SAMP1/YitFc小鼠会自发地患上慢性、不连续、透壁性回肠炎，其许多特征与克罗恩病相似。本研究的目的是确定抗生素治疗在SAMP1/YitFc回肠炎小鼠模型中的效果并阐明其作用机制。在回肠炎发生前（预防方案）或回肠炎完全形成后（治疗方案），小鼠经口接受环丙沙星和甲硝唑治疗。采集末端回肠进行组织学评分，并分离固有层和肠系膜淋巴结细胞以分析活化标志物和细胞因子的产生。与未治疗的对照小鼠相比，抗生素治疗在预防方案（减轻40%，p < 0.05）和治疗方案（减轻25%，p < 0.01）中均显著降低了回肠炎的严重程度。这些作用与抗生素治疗小鼠肠系膜淋巴结中CD4(+)/CD45RB(高)淋巴细胞百分比降低以及干扰素 -γ（预防：0.53 ± 0.21对1.84 ± 0.04纳克/毫升，p < 0.05；治疗：8.4 ± 0.4对12.4 ± 0.7纳克/毫升，p < 0.005）和肿瘤坏死因子（预防：61.5 ± 13对134 ± 19皮克/毫升，p < 0.01；治疗：333.5 ± 11对496 ± 20皮克/毫升，p < 0.001）的产生减少有关。抗生素治疗后，活化的固有层淋巴细胞数量也减少了。总之，抗生素治疗通过一种涉及下调活化的肠道淋巴细胞和抑制肠道Th1细胞因子产生的机制，显著改善了SAMP1/YitFc小鼠回肠炎的严重程度。
Resident intestinal bacteria likely play an important role in the pathogenesis of Crohn's disease through their interaction with the gut immune system. SAMP1/YitFc mice spontaneously develop chronic, discontinuous, transmural ileitis with many features similar to Crohn's disease. The aim of this study was to determine the effects and elucidate the mechanisms of action of antibiotic treatment in the SAMP1/YitFc mouse model of ileitis. Mice were treated orally with ciprofloxacin and metronidazole before the development of ileitis (prevention protocol) or after ileitis was fully established (treatment protocol). Terminal ilea were harvested for histological scoring, and lamina propria and mesenteric lymph node cells were isolated for analysis of activation markers and cytokine production. Antibiotic therapy significantly decreased the severity of ileitis both in the prevention (40% reduction, p < 0.05) and the treatment (25% reduction, p < 0.01) protocols, compared with untreated, control mice. These effects were associated with a decreased percentage of CD4(+)/CD45RB(high) lymphocytes in mesenteric lymph nodes of antibiotic-treated mice, as well as decreased production of IFN-gamma (prevention: 0.53 +/- 0.21 vs 1.84 +/- 0.04 ng/ml, p < 0.05; treatment: 8.4 +/- 0.4 vs 12.4 +/- 0.7 ng/ml, p < 0.005) and TNF (prevention: 61.5 +/- 13 vs 134 +/- 19 pg/ml, p < 0.01; treatment: 333.5 +/- 11 vs 496 +/- 20 pg/ml, p < 0.001). The number of activated lamina propria lymphocytes was also reduced after antibiotic treatment. In conclusion, antibiotic therapy significantly ameliorates the severity of ileitis in SAMP1/YitFc mice by a mechanism involving down-regulation of activated gut lymphocytes and inhibition of intestinal Th1 cytokine production.