Abreu-Martin M T, Vidrich A, Lynch D H, Targan S R
Inflammatory Bowel Disease Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
J Immunol. 1995 Nov 1;155(9):4147-54.
Colonic epithelial cell injury is the common manifestation of inflammatory diseases of the bowel. One form of epithelial injury is apoptosis. In our study, we investigated the mechanism leading to apoptosis in HT-29 cells in response to TNF-alpha and ligation of Fas Ag. HT-29 displayed a dual response to TNF-alpha and Fas Ag ligation: in combination with IFN-gamma, HT-29 cells underwent apoptosis, whereas independently, these factors stimulated secretion of IL-8. We used this model of immune-mediated epithelial cell injury to elucidate the signals leading to apoptosis in response to TNF-alpha and Fas Ag ligation compared with the signals leading to induction of IL-8 secretion. The model was further used to distinguish signaling differences between TNF-alpha receptors and the Fas Ag in this cell line. The experiments presented here demonstrate that Fas Ag ligation alone led to production of IL-8 by colonic epithelial cells and represented another function mediated by Fas Ag in addition to apoptosis. This study shows that the pathways leading to cell death and IL-8 production in response to Fas Ag ligation and TNF-alpha were similar with regard to their requirements for new gene expression, protein synthesis, and protein kinase activity. Specifically, new gene expression and protein synthesis were not necessary for TNF-alpha- and Fas Ag-mediated apoptosis, but were necessary for TNF-alpha- and Fas Ag-mediated IL-8 secretion. Tyrosine protein kinase phosphorylation was necessary to signal secretion of IL-8 in response to both agonists but it was not necessary for apoptosis. In spite of the similarities between these two agonists, the kinetics of apoptosis via Fas Ag were significantly more rapid than through the TNF-alpha receptor and serve to distinguish these two signals.
结肠上皮细胞损伤是肠道炎症性疾病的常见表现。上皮损伤的一种形式是细胞凋亡。在我们的研究中，我们调查了HT - 29细胞在肿瘤坏死因子-α（TNF-α）和Fas抗原连接作用下导致细胞凋亡的机制。HT - 29细胞对TNF-α和Fas抗原连接呈现双重反应：与干扰素-γ（IFN-γ）联合作用时，HT - 29细胞发生凋亡，而单独作用时，这些因子刺激白细胞介素-8（IL-8）的分泌。我们利用这种免疫介导的上皮细胞损伤模型，来阐明与导致IL-8分泌的信号相比，TNF-α和Fas抗原连接作用下导致细胞凋亡的信号。该模型还被用于区分该细胞系中TNF-α受体和Fas抗原之间的信号差异。此处展示的实验表明，单独的Fas抗原连接导致结肠上皮细胞产生IL-8，这代表了Fas抗原除细胞凋亡外介导的另一功能。这项研究表明，在对Fas抗原连接和TNF-α反应中，导致细胞死亡和IL-8产生的信号通路在对新基因表达、蛋白质合成和蛋白激酶活性的需求方面是相似的。具体而言，新基因表达和蛋白质合成对于TNF-α和Fas抗原介导的细胞凋亡不是必需的，但对于TNF-α和Fas抗原介导的IL-8分泌是必需的。酪氨酸蛋白激酶磷酸化对于两种激动剂介导的IL-8分泌是必需的信号，但对于细胞凋亡不是必需的。尽管这两种激动剂之间存在相似性，但通过Fas抗原介导的细胞凋亡动力学明显比通过TNF-α受体介导的更快，这有助于区分这两种信号。
