Vetrano Stefania, Rescigno Maria, Cera Maria Rosaria, Correale Carmen, Rumio Cristiano, Doni Andrea, Fantini Massimo, Sturm Andreas, Borroni Elena, Repici Alessandro, Locati Massimo, Malesci Alberto, Dejana Elisabetta, Danese Silvio
Division of Gastroenterology, Istituto di Ricerca e Cura a Carattere Scientifico Istituto Clinico Humanitas, University of Milan, Rozzano, Italy.
Gastroenterology. 2008 Jul;135(1):173-84. doi: 10.1053/j.gastro.2008.04.002. Epub 2008 Apr 11.
BACKGROUND & AIMS: Junctional adhesion molecule-A (JAM-A) is localized at the tight junctions and controls leukocyte migration into the tissues. However, its functional role in inflammatory bowel disease (IBD) is unexplored.
Control, Crohn's disease (CD), and ulcerative colitis (UC) tissue specimens were studied for JAM-A expression, as well as the colon of mice given dextran sodium sulfate (DSS). Wild-type and JAM-A(-/-), Tie-2-Cre-JAM-A(-/-) (endothelial/hematopoietic-specific JAM inactivation) mice were studied for susceptibility to DSS. Disease activity and colonic inflammation were assessed using a disease activity index histology and endoscopy, and mucosal cytokines were measured by enzyme-linked immunosorbent assay. JAM-A function was investigated by RNA silencing in epithelial cells, and apoptosis was measured.
In both CD and UC, as well as in experimental colitis, there is a loss of epithelial but not endothelial JAM-A expression. Deletion of JAM-A results in a dramatic increase in susceptibility to DSS colitis, as assessed by weight loss, disease activity index, histologic and endoscopic severity, and strikingly high mortality rates. This is not caused by the absence of JAM-A in the endothelial or hematopoietic compartments because Tie-2-Cre-JAM-A(-/-) mice are no more susceptible to DSS colitis than wild-type animals. JAM-A(-/-) mice displayed increased intestinal permeability and inflammatory cytokine production, and marked epithelial apoptosis. Silencing of JAM-A in intestinal epithelial cells resulted in increased permeability in vitro.
Our results show a nonredundant and novel role of JAM-A in controlling mucosal homeostasis by regulating the integrity and permeability of epithelial barrier function.
连接黏附分子A（JAM-A）定位于紧密连接处，控制白细胞向组织内迁移。然而，其在炎症性肠病（IBD）中的功能作用尚未得到探索。
研究对照、克罗恩病（CD）和溃疡性结肠炎（UC）组织标本中JAM-A的表达，以及给予葡聚糖硫酸钠（DSS）的小鼠的结肠组织。研究野生型和JAM-A基因敲除（-/-）、Tie-2-Cre-JAM-A基因敲除（-/-）（内皮/造血特异性JAM失活）小鼠对DSS的易感性。使用疾病活动指数、组织学和内窥镜检查评估疾病活动度和结肠炎症，并通过酶联免疫吸附测定法测量黏膜细胞因子。通过上皮细胞中的RNA沉默研究JAM-A的功能，并检测细胞凋亡。
在CD和UC以及实验性结肠炎中，上皮细胞而非内皮细胞中的JAM-A表达均缺失。通过体重减轻、疾病活动指数、组织学和内窥镜检查严重程度以及极高的死亡率评估，JAM-A的缺失导致对DSS结肠炎易感性显著增加。这不是由内皮或造血区室中JAM-A的缺失引起的，因为Tie-2-Cre-JAM-A（-/-）小鼠对DSS结肠炎的易感性并不比野生型动物更高。JAM-A（-/-）小鼠表现出肠道通透性增加、炎性细胞因子产生增加以及明显的上皮细胞凋亡。肠道上皮细胞中JAM-A的沉默导致体外通透性增加。
我们的结果表明JAM-A在通过调节上皮屏障功能的完整性和通透性来控制黏膜稳态方面具有非冗余的新作用。
