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/jci33194
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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
IL-22的表达在包括炎性肠病（IBD）在内的几种人类炎性病症中被诱导。IL-22受体的表达仅限于先天免疫细胞;然而，IL-22在结肠炎中的作用尚未确定。我们开发了我们认为是一种新型的基于显微注射的局部基因传递系统，能够靶向发炎的肠道。使用这种方法，我们证明了在Th 2介导的结肠炎小鼠模型中IL-22介导的先天免疫途径激活的治疗效力，该模型诱导具有与IBD溃疡性结肠炎（UC）相似特征的疾病。IL-22基因递送增强了结肠上皮细胞内特异性STAT 3活化，并诱导了粘液相关分子的STAT 3依赖性表达和粘液产生杯状细胞的恢复。重要的是，IL-22基因递送导致局部肠道炎症的快速改善。IL-22对疾病的改善是通过增强粘液产生介导的。此外，局部基因递送用于通过过表达IL-22结合蛋白来抑制IL-22活性。在葡聚糖硫酸钠诱导的急性结肠炎模型的恢复期，用IL-22结合蛋白治疗抑制杯状细胞恢复。这些数据证明了我们认为IL-22在肠道中的新功能，并表明局部IL-22基因递送系统治疗UC的效力。
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.