Fries Walter, Muja Carmelo, Crisafulli Carmela, Costantino Giuseppe, Longo Giuseppe, Cuzzocrea Salvatore, Mazzon Emanuela
Dipartimento di Medicina Interna e Terapia Medica, Sezione di Farmacologia, Università di Messina, Messina, Italy.
Int J Med Sci. 2008 Jul 3;5(4):169-80. doi: 10.7150/ijms.5.169.
Loss of epithelial barrier integrity is considered an early step in the pathogenesis of Crohn's disease (CD), and the rate of enterocyte apoptosis is one of the determinants of the intestinal barrier function. Tumor necrosis factor-alpha (TNF-alpha), one of the major proinflammatory mediators in CD, is one of the extrinsic signals which initiate apoptosis of enterocytes. The aim of this study was to investigate the early effects of experimental colitis on enterocyte apoptosis, and the effects of two anti-TNF treatments, infliximab (IFX) and etanercept (ETC). In addition, the importance of receptor I for TNF was tested in TNFR-1(-/- )mice. Circulating TNF-alpha levels were effectively reduced by IFX and ETC (p<0.01, both) at 3 and 6 h. Apoptosis of the ileal enterocytes, assessed by TUNEL staining, staining for Fas-ligand, and bax, increased at 3 and 6h. These alterations were prevented by both anti-TNF strategies, and in TNFR-1(-/-) animals. The anti-apoptotic protein Bcl-2 was expressed in the ileal epithelium under control conditions, but was suppressed in DNB-colitis. Expression of Bcl-2 was maintained in both anti-TNF treatments and TNFR-1(-/-) mice.DNB colitis induced a very early, rapid increase of enterocyte apoptosis. Both anti-TNF strategies, IFX and ETC, were equally effective in suppressing enterocyte apoptosis, most likely by inactivation of circulating TNF-alpha.
上皮屏障完整性的丧失被认为是克罗恩病（CD）发病机制的早期步骤，肠上皮细胞凋亡率是肠道屏障功能的决定因素之一。肿瘤坏死因子-α（TNF-α）是CD中主要的促炎介质之一，是启动肠上皮细胞凋亡的外在信号之一。本研究的目的是探讨实验性结肠炎对肠上皮细胞凋亡的早期影响，以及两种抗TNF治疗（英夫利昔单抗（IFX）和依那西普（ETC））的效果。此外，在TNFR-1（-/-）小鼠中检测了TNF受体I的重要性。IFX和ETC在3小时和6小时时均有效降低了循环TNF-α水平（两者p<0.01）。通过TUNEL染色、Fas配体染色和bax评估，回肠肠上皮细胞凋亡在3小时和6小时时增加。两种抗TNF策略以及在TNFR-1（-/-）动物中均可防止这些改变。抗凋亡蛋白Bcl-2在对照条件下在回肠上皮中表达，但在二硝基苯磺酸（DNB）结肠炎中受到抑制。在两种抗TNF治疗和TNFR-1（-/-）小鼠中，Bcl-2的表达均得以维持。DNB结肠炎诱导肠上皮细胞凋亡非常早期、快速增加。两种抗TNF策略，IFX和ETC，在抑制肠上皮细胞凋亡方面同样有效，很可能是通过使循环TNF-α失活。
