Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Ratzeburger Allee 160, D-23538 Lübeck, Germany.
Am J Pathol. 2010 Apr;176(4):1816-27. doi: 10.2353/ajpath.2010.090461. Epub 2010 Feb 4.
In inflammatory bowel diseases (IBD), intestinal epithelial cells (IECs) are involved in the outbalanced immune responses toward luminal antigens. However, the signals responsible for this proinflammatory capacity of IECs in IBD remain unclear. The CD40/CD40L interaction activates various pathways in immune and nonimmune cells related to inflammation and was shown to be critical for the development of IBD. Here we demonstrate CD40 expression within IECs during active IBD. Endoscopically obtained biopsies taken from Crohn's disease (n = 112) and ulcerative colitis patients (n = 67) consistently showed immunofluorescence staining for CD40 in IECs of inflamed ileal or colonic mucosa. In noninvolved mucosa during active disease, tissue obtained during Crohn's disease or ulcerative colitis in remission and biopsies from healthy controls (n = 38) IECs almost entirely lacked CD40 staining. Flow cytometry and RT-PCR analysis using different intestinal epithelial cell lines (HT29, SW480, and T84) showed IFN-gamma to effectively induce CD40 in IECs. Cells were virtually unresponsive to LPS or whole E. coli regarding CD40 expression. In addition, a moderate induction of CD40 was found in response to TNF-alpha, which exerted synergistical effects with IFN-gamma. CD40 ligation by CD40L-transfected murine fibroblasts or soluble CD40L increased the secretion of IL-8 in IFN-gamma pretreated HT29 cells. Our findings provide evidence for the epithelial expression and modulation of CD40 in IBD-affected mucosa and indicate its involvement in the proinflammatory function of IECs.
在炎症性肠病（IBD）中，肠上皮细胞（IEC）参与了对腔抗原的失衡免疫反应。然而，导致 IBD 中 IEC 这种促炎能力的信号仍然不清楚。CD40/CD40L 相互作用激活了与炎症相关的免疫和非免疫细胞中的各种途径，并被证明对 IBD 的发展至关重要。在这里，我们在活动性 IBD 期间证明了 CD40 在 IEC 中的表达。从克罗恩病（n=112）和溃疡性结肠炎患者（n=67）获得的内镜活检均显示，在炎症性回肠或结肠黏膜的 IEC 中存在 CD40 的免疫荧光染色。在活动性疾病期间非受累的黏膜中，克罗恩病或溃疡性结肠炎缓解期间获得的组织以及健康对照者（n=38）的活检中，IEC 几乎完全缺乏 CD40 染色。使用不同的肠上皮细胞系（HT29、SW480 和 T84）进行流式细胞术和 RT-PCR 分析显示，IFN-γ可有效诱导 IEC 中的 CD40。细胞对 LPS 或整个大肠杆菌的 CD40 表达几乎没有反应。此外，还发现 TNF-α可适度诱导 CD40 的表达，其与 IFN-γ具有协同作用。CD40L 转染的鼠成纤维细胞或可溶性 CD40L 对 CD40 的交联增加了 IFN-γ预处理的 HT29 细胞中 IL-8 的分泌。我们的研究结果为 IBD 受累黏膜中 CD40 的上皮表达和调节提供了证据，并表明其参与了 IEC 的促炎功能。
