Section of Pediatric Surgery, Department of Surgery, University of Michigan Medical School and C S Mott Children's Hospital, Ann Arbor, Michigan MI 48109-5245, USA.
Am J Physiol Gastrointest Liver Physiol. 2012 Jan 15;302(2):G236-49. doi: 10.1152/ajpgi.00142.2011. Epub 2011 Nov 10.
Epidermal growth factor (EGF) and tumor necrosis factor-α (TNF-α) signaling are critical for effective proliferative and apoptotic actions; however, little is known about the codependency of these signaling pathways in the intestinal epithelium. Because total parenteral nutrition (TPN) is associated with loss of intestinal epithelial cell (IEC) proliferation and increased apoptosis, we utilized a mouse model to explore these transactivation pathways in small bowel epithelium. Mice underwent intravenous cannulation and were given enteral nutrition or TPN for 7 days. Outcomes included IEC proliferation, apoptosis, and survival. To address transactivation or dependence of EGF and TNF on IEC physiology, TNF-α receptor knockout (KO) mice, TNFR1-KO, R2-KO, or R1R2-double KO, were used. Exogenous EGF and pharmacological blockade of ErbB1 were performed in other groups to examine the relevance of the ErB1 pathway. TPN increased IEC TNFR1 and decreased EGF and ErbB1 abundance. Loss of IEC proliferation was prevented by exogenous EGF or blockade of TNFR1. However, EGF action was prevented without effective TNFR2 signaling. Also, blockade of TNFR1 could not prevent loss of IEC proliferation without effective ErbB1 signaling. TPN increased IEC apoptosis and was due to increased TNFR1 signaling. Exogenous EGF or blockade of TNFR1 could prevent increased apoptosis, and both pathways were dependent on effective ErbB1 signaling. Exogenous EGF prevented increased apoptosis in mice lacking TNFR2 signaling. TPN mice had significantly decreased survival vs. controls, and this was associated with the TNFR1 signaling pathway. We concluded that these findings identify critical mechanisms that contribute to TPN-associated mucosal atrophy via altered TNF-α/EGF signaling. It emphasizes the importance of both TNFR1 and TNFR2 pathways, as well as the strong interdependence on an intact EGF/ErbB1 pathway.
表皮生长因子（EGF）和肿瘤坏死因子-α（TNF-α）信号对于有效的增殖和凋亡作用至关重要；然而，关于这些信号通路在肠道上皮细胞中的相互依存关系知之甚少。由于全胃肠外营养（TPN）与肠上皮细胞（IEC）增殖减少和凋亡增加有关，我们利用小鼠模型来探索小肠上皮细胞中的这些转导途径。小鼠接受静脉插管，并给予肠内营养或 TPN 治疗 7 天。结果包括 IEC 增殖、凋亡和存活。为了研究 EGF 和 TNF 对 IEC 生理学的转导或依赖性，使用了 TNF-α受体敲除（KO）小鼠、TNFR1-KO、R2-KO 或 R1R2 双 KO。在其他组中进行外源性 EGF 和 ErbB1 药理学阻断，以检查 ErbB1 途径的相关性。TPN 增加了 IEC 的 TNFR1，降低了 EGF 和 ErbB1 的丰度。外源性 EGF 或 TNFR1 阻断可预防 IEC 增殖减少。然而，没有有效的 TNFR2 信号，EGF 作用就会被阻止。另外，没有有效的 ErbB1 信号，阻断 TNFR1 也不能预防 IEC 增殖减少。TPN 增加了 IEC 凋亡，这是由于 TNFR1 信号增加所致。外源性 EGF 或 TNFR1 阻断可预防凋亡增加，两条途径均依赖于有效的 ErbB1 信号。外源性 EGF 可预防缺乏 TNFR2 信号的小鼠发生凋亡增加。与对照组相比，TPN 小鼠的存活率显著降低，这与 TNFR1 信号通路有关。我们的结论是，这些发现确定了通过改变 TNF-α/EGF 信号导致 TPN 相关黏膜萎缩的关键机制。它强调了 TNFR1 和 TNFR2 途径的重要性，以及对完整的 EGF/ErbB1 途径的强烈相互依赖性。
