Sugimoto Ken, Ogawa Atsuhiro, Mizoguchi Emiko, Shimomura Yasuyo, Andoh Akira, Bhan Atul K, Blumberg Richard S, Xavier Ramnik J, Mizoguchi Atsushi
Experimental Pathology Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
J Clin Invest. 2008 Feb;118(2):534-44. doi: 10.1172/JCI33194.
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.
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性疾病中表达上调。IL-22受体的表达仅限于天然免疫细胞；然而，IL-22在结肠炎中的作用尚未明确。我们开发了一种基于显微注射的新型局部基因递送系统，该系统能够靶向炎症肠道。利用这种方法，我们在Th2介导的结肠炎小鼠模型中证明了IL-22介导的天然免疫途径激活具有治疗潜力，该模型诱导的疾病具有与IBD溃疡性结肠炎（UC）相似的特征。IL-22基因递送特异性增强了结肠上皮细胞内的信号转导和转录激活因子3（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恢复。重要的是，IL-22基因递送导致局部肠道炎症迅速改善。IL-22对疾病的改善是通过增强黏液分泌介导的。此外，通过局部基因递送过表达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阶段，用IL-22结合蛋白治疗可抑制杯状细胞的恢复。这些数据证明了我们认为的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的潜力。
