IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis
IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis
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DOI：
10.1172/jc133194
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发表时间：
2008-02-01
影响因子：
15.9
通讯作者：
Mizoguchi, Atsushi
中科院分区：
文献类型：
--
作者：
Sugimoto, Ken;Ogawa, Atsuhiro;Mizoguchi, Atsushi
白细胞介素 - 22（IL - 22）在包括炎症性肠病（IBD）在内的多种人类炎症疾病中表达被诱导。IL - 22受体的表达局限于天然免疫细胞；然而，IL - 22在结肠炎中的作用尚未明确。我们开发了一种我们认为新颖的基于显微注射的局部基因传递系统，它能够靶向发炎的肠道。利用这种方法，我们在一种由Th2介导的结肠炎小鼠模型中证明了IL - 22介导的天然免疫通路激活具有治疗效力，该模型所诱导疾病的特征与IBD溃疡性结肠炎（UC）相似。IL - 22基因传递特异性地增强了结肠上皮细胞内的STAT3激活，并诱导了黏液相关分子的STAT3依赖性表达以及产生黏液的杯状细胞的修复。重要的是，IL - 22基因传递导致局部肠道炎症迅速缓解。IL - 22对疾病的缓解是通过增强黏液产生来介导的。此外，通过局部基因传递过表达IL - 22结合蛋白来抑制IL - 22的活性。在葡聚糖硫酸钠诱导的急性结肠炎模型的恢复阶段，用IL - 22结合蛋白治疗抑制了杯状细胞的修复。这些数据证明了我们所认为的IL - 22在肠道中的一种新功能，并表明局部IL - 22基因传递系统在治疗UC方面的潜力。
Expression of IL-22 is induced in several human inflammatory conditions, including inflammatory bowel disease (IBD). Expression of the IL-22 receptor is restricted to innate immune cells; however, the role of IL-22 in colitis has not yet been defined. We developed what we believe to be a novel microinjection-based local gene-delivery system that is capable of targeting the inflamed intestine. Using this approach, we demonstrated a therapeutic potency for IL-22-mediated activation of the innate immune pathway in a mouse model of Th2-mediated colitis that induces disease with characteristics similar to that of IBD ulcerative colitis (UC). IL-22 gene delivery enhanced STAT3 activation specifically within colonic epithelial cells and induced both STAT3-dependent expression of mucus-associated molecules and restitution of mucus-producing goblet cells. Importantly, IL-22 gene delivery led to rapid amelioration of local intestinal inflammation. The amelioration of disease by IL-22 was mediated by enhanced mucus production. In addition, local gene delivery was used to inhibit IL-22 activity through overexpression of IL-22-binding protein. Treatment with IL-22-binding protein suppressed goblet cell restitution during the recovery phase of a dextran sulfate sodium-induced model of acute colitis. These data demonstrate what we believe to be a novel function for IL-22 in the intestine and suggest the potency of a local IL-22 gene-delivery system for treating UC.