Mizoguchi Emiko
Center for the Study of Inflammatory Bowel Disease, Gastroenterology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, USA.
Gastroenterology. 2006 Feb;130(2):398-411. doi: 10.1053/j.gastro.2005.12.007.
BACKGROUND & AIMS: Dysregulated host/microbial interactions appear to play a central role in the development of inflammatory bowel disease (IBD). However, molecular events leading to the dysregulation have not yet been defined fully. Studies were designed to characterize a key molecule that is involved in the dysregulation.
Colonic mucosal RNA from C57BL/6 mice on days 4 and 8 with administration of 4% dextran sulfate sodium for 5 days were subjected to DNA microarray analysis. Chitinase 3-like-1 (CHI3L1) messenger RNA and protein expressions were examined by reverse-transcription polymerase chain reaction and immunohistochemistry. A gentamicin protection assay of Salmonella typhimurium was performed using epithelial cell lines that are engineered genetically to overexpress or lack mouse CHI3L1. To examine the functional role of CHI3L1 in vivo, anti-CHI3L1 antibody was administered into the dextran sulfate sodium colitis model.
Microarray analysis identified that CHI3L1 is up-regulated specifically in inflamed mucosa. The expression of CHI3L1 protein clearly was detectable in lamina propria and colonic epithelial cells (CECs) in several murine colitis models and ulcerative colitis and Crohn's disease patients but absent in normal controls. The gentamicin protection assays using intracellular bacteria showed that CHI3L1 is required for the enhancement of adhesion and internalization of these bacteria in CEC. In vivo neutralization experiments showed that CHI3L1 contributes to the facilitation of bacterial invasion into the intestinal mucosa and the development of acute colitis.
CHI3L1 plays a pathogenic role in colitis, presumably by enhancing the adhesion and invasion of bacteria on/into CEC. Inhibition of CHI3L1 activity would be a novel therapeutic approach for IBD.
宿主/微生物相互作用失调似乎在炎症性肠病（IBD）的发展中起核心作用。然而，导致这种失调的分子事件尚未完全明确。本研究旨在鉴定参与这种失调的关键分子。
对给予4%葡聚糖硫酸钠5天的第4天和第8天的C57BL/6小鼠的结肠黏膜RNA进行DNA微阵列分析。通过逆转录聚合酶链反应和免疫组织化学检测几丁质酶3样-1（CHI3L1）信使核糖核酸和蛋白表达。使用经基因工程改造过表达或缺失小鼠CHI3L1的上皮细胞系对鼠伤寒沙门氏菌进行庆大霉素保护试验。为了在体内检测CHI3L1的功能作用，将抗CHI3L1抗体注入葡聚糖硫酸钠结肠炎模型。
微阵列分析确定CHI3L1在炎症黏膜中特异性上调。在几种小鼠结肠炎模型、溃疡性结肠炎和克罗恩病患者的固有层和结肠上皮细胞（CEC）中可清楚检测到CHI3L1蛋白表达，但在正常对照中不存在。使用胞内细菌的庆大霉素保护试验表明，CHI3L1是这些细菌在CEC中黏附增强和内化所必需的。体内中和实验表明，CHI3L1有助于促进细菌侵入肠黏膜和急性结肠炎的发展。
CHI3L1在结肠炎中起致病作用，可能是通过增强细菌在CEC上的黏附及侵入CEC。抑制CHI3L1活性可能是IBD的一种新治疗方法。
