Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis
Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis
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DOI：
10.1053/gast.2002.32994
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发表时间：
2002-05-01
期刊：
影响因子：
29.4
通讯作者：
Raz, E
中科院分区：
文献类型：
--
作者：
Rachmilewitz, D;Karmeli, F;Raz, E
背景和目标：黏膜屏障受损、细胞因子失衡和CD 4（+）T细胞失调在实验性结肠炎和人类炎症性肠病的发病机制中起重要作用。免疫刺激性DNA序列（ISS-DNA）及其合成的寡核苷酸类似物（ISS-ODN）来源于细菌DNA，是全身和粘膜部位的先天免疫的有效激活剂，并且可以拯救细胞免于由不同试剂造成的死亡。我们假设ISS-DNA的这些联合作用可以抑制化学诱导的结肠炎中结肠粘膜的损伤，从而限制随后的肠道炎症。研究方法：在葡聚糖硫酸钠诱导的结肠炎和2种半抗原诱导的Balb/c小鼠结肠炎模型中评估ISS-ODN施用的保护和抗炎作用。类似地，在IL-10敲除小鼠中发生的自发性结肠炎中评估ISS-ODN的这些作用。结果如下：在所有实验性和自发性结肠炎模型中，ISS-ODN给药改善了结肠炎症的临床、生化和组织学评分。ISS-ODN给药抑制结肠促炎细胞因子和趋化因子的诱导，并抑制葡聚糖硫酸钠和半抗原诱导的结肠炎中结肠基质金属蛋白酶的诱导。结论：由于结肠持续暴露于细菌DNA，这些发现表明免疫刺激DNA在胃肠道中具有生理抗炎作用。免疫刺激DNA值得进一步评价用于治疗人类炎症性肠病。
Background & Aims: Impaired mucosal barrier, cytokine imbalance, and dysregulated CD4(+) T cells play important roles in the pathogenesis of experimental colitis and human inflammatory bowel disease. Immunostimulatory DNA sequences (ISS-DNA) and their synthetic oligonucleotide analogs (ISS-ODNs) are derived from bacterial DNA, are potent activators of innate immunity at systemic and mucosal sites, and can rescue cells from death inflicted by different agents. We hypothesized that these combined effects of ISS-DNA could inhibit the damage to the colonic mucosa in chemically induced colitis and thereby limit subsequent intestinal inflammation. Methods: The protective and the anti-inflammatory effect of ISS-ODN administration were assessed in dextran sodium sulfate-induced colitis and in 2 models of hapten-induced colitis in Balb/c mice. Similarly, these effects of ISS-ODN were assessed in spontaneous colitis occurring in IL-10 knockout mice. Results: In all models of experimental and spontaneous colitis examined, ISS-ODN administration ameliorated clinical, biochemical, and histologic scores of colonic inflammation. ISS-ODN administration inhibited the induction of colonic proinflammatory cytokines and chemokines and suppressed the induction of colonic matrix metalloproteinases in both dextran sodium sulfate- and hapten-induced colitis. Conclusions: As the colon is continuously exposed to bacterial DNA, these findings suggest a physiologic, anti-inflammatory role for immunostimulatory DNA in the GI tract. Immunostimulatory DNA deserves further evaluation for the treatment of human inflammatory bowel disease.