TNF-α neutralization ameliorates the severity of murine Crohn's-like ileitis by abrogation of intestinal epithelial cell apoptosis
TNF-α neutralization ameliorates the severity of murine Crohn's-like ileitis by abrogation of intestinal epithelial cell apoptosis
复制标题
DOI：
10.1073/pnas.1432897100
复制
发表时间：
2003-07-08
影响因子：
11.1
通讯作者：
Cominelli, F
中科院分区：
文献类型：
--
作者：
Marini, M;Bamias, G;Cominelli, F
肿瘤坏死因子α（TNF-α）是程序性细胞死亡的重要介质，并且TNF-α阻断显著改善几种炎性病症（包括克罗恩病（CD），特发性炎性肠病之一）中的疾病严重程度。然而，抗TNF-α治疗CD的确切作用机制仍知之甚少。SAMP 1/YitFc小鼠发生自发性回肠炎，在组织学特征以及对常规治疗的反应方面与人CD相似。在本报告中，我们测试了新的假设，即抗TNF-α治疗CD的有益作用是由一种机制介导的，该机制涉及肠上皮细胞（IEC）凋亡的下调。与单克隆抗TNF-α抗体在人CD中的功效类似，与注射同种型对照抗体的小鼠相比，将嵌合抗鼠TNF-α抗体单次注射到SAMP 1/YitFc小鼠中导致肠道炎症和上皮细胞损伤的显著抑制。通过碘化丙啶染色和DNA梯状化评估，这些作用与新鲜分离的IEC细胞凋亡的显著减少相关。相反，与对照组相比，在抗TNF-α治疗的小鼠中观察到固有层单核细胞凋亡增加。这些结果通过使用末端脱氧核苷酸转移酶介导的dUTP-生物素缺口末端标记测定在体内得到证实。此外，与对照抗体相比，TNF-α的中和降低了来自SAMP 1/YitFc小鼠的IEC中的膜结合FAS/CD 95表达。这些数据证明了抗TNF-α治疗的新的作用机制，其涉及粘膜细胞凋亡的稳态调节，这导致CD中通常发现的慢性炎症的净减少。
Tumor necrosis factor alpha (TNF-alpha) is an important mediator of programmed cell death, and TNF-a blockade significantly improves disease severity in several inflammatory conditions, including Crohn's disease (CD), one of the idiopathic inflammatory bowel diseases. However, the precise mechanism(s) of action of anti-TNF-alpha therapy in CD remains poorly understood. SAMP1/YitFc mice develop a spontaneous ileitis with similarities to human CD in regard to histological features as well as response to conventional treatments. In this report, we tested the novel hypothesis that the beneficial effects of anti-TNF-a therapy in CD are mediated by a mechanism that involves down-regulation of intestinal epithelial cell (IEC) apoptosis. Similar to the efficacy of monoclonal anti-TNF-alpha antibodies in human CD, a single injection of a chimeric anti-murine TNF-a antibody into SAMP1/YitFc mice resulted in a marked suppression of intestinal inflammation and epithelial cell damage compared with mice injected with an isotype control antibody. These effects were associated with a significant reduction in apoptosis of freshly isolated IEC as assessed by propidium iodide staining and DNA laddering. In contrast, an increase in lamina propria mononuclear cell apoptosis was observed in anti-TNF-alpha-treated mice compared with control. These results were confirmed in vivo by using the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling-assay. In addition, neutralization of TNF-a reduced membrane bound FAS/CD95 expression in IEC from SAMP1/YitFc mice compared with control antibody. These data demonstrate a novel mechanism of action of anti-TNF-a therapy that involves homeostatic regulation of mucosal cell apoptosis, which results in the net decrease of chronic inflammation typically found in CD.