Pryhuber G S, Huyck H L, Staversky R J, Finkelstein J N, O'Reilly M A
Department of Pediatrics and Environmental Medicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
Am J Respir Cell Mol Biol. 2000 Feb;22(2):150-6. doi: 10.1165/ajrcmb.22.2.3783.
Tumor necrosis factor (TNF) receptor (TNFR)-associated factors 1 and 2 (TRAF1 and TRAF2) and inhibitor of apoptosis proteins cIAP1 (MIHB) and cIAP2 (MIHC) were recently identified as proteins that associate with the TNF-alpha receptors TNFRI (p55) and TNFRII (p75) and inhibit TNF-alpha-induced programmed cell death or apoptosis. In the original reports, TRAF1 expression, unlike the ubiquitous TRAF2, was restricted to specific tissues in the lung, spleen, and testis. TNF-alpha is increased in the lung in many forms of pulmonary disease. In the current study, Western analysis, immunohistochemistry, and ribonuclease protection assays were used to determine whether TNF-alpha regulates the expression of these TNFR-associated proteins in lung cells. We demonstrate for the first time TNF-alpha dose-dependent induction of TRAF1 protein and messenger RNA (mRNA) in human H441 and A549 pulmonary adenocarcinoma cell lines, as well as in lung cells of C57BL/6J mice after intratracheal administration of TNF-alpha. In contrast to the epithelial cells, TRAF1 was not induced by TNF-alpha in U937 cells, a human monocytic cell line, suggesting cell type-specific regulation. Similarly, cIAP2 mRNA was induced by TNF-alpha in both H441 and A549 pulmonary epithelial cells but not in U937 cells. TNF-alpha is a primary mediator of acute pulmonary inflammation and contributes to the pathophysiology of chronic lung diseases such as bronchopulmonary dysplasia (BPD), a fibrotic disease of prematurely born infants. Immunohistochemical staining of human neonatal lung tissue demonstrated increased TRAF1 in lungs of infants dying of pneumonia or BPD in comparison with those dying of congenital malformation. These studies support the hypothesis that the TRAF1 and cIAP2 genes are highly regulated in pulmonary cells and may play a role in human lung disease.
肿瘤坏死因子（TNF）受体（TNFR）相关因子1和2（TRAF1和TRAF2）以及凋亡抑制蛋白cIAP1（MIHB）和cIAP2（MIHC）最近被鉴定为与肿瘤坏死因子-α受体TNFR I（p55）和TNFR II（p75）相关的蛋白，它们可抑制肿瘤坏死因子-α诱导的程序性细胞死亡或凋亡。在最初的报道中，与广泛存在的TRAF2不同，TRAF1的表达仅限于肺、脾和睾丸中的特定组织。在多种肺部疾病中，肺内的肿瘤坏死因子-α水平会升高。在本研究中，采用蛋白质免疫印迹分析、免疫组织化学和核糖核酸酶保护试验来确定肿瘤坏死因子-α是否调节肺细胞中这些TNFR相关蛋白的表达。我们首次证明，在人H441和A549肺腺癌细胞系中，以及在经气管内给予肿瘤坏死因子-α后的C57BL/6J小鼠肺细胞中，肿瘤坏死因子-α可剂量依赖性地诱导TRAF1蛋白和信使核糖核酸（mRNA）的表达。与上皮细胞不同，在人单核细胞系U937细胞中，肿瘤坏死因子-α不会诱导TRAF1的表达，这表明存在细胞类型特异性调节。同样，在H441和A549肺上皮细胞中，肿瘤坏死因子-α可诱导cIAP2 mRNA的表达，但在U937细胞中则不会。肿瘤坏死因子-α是急性肺部炎症的主要介质，并且在慢性肺部疾病如支气管肺发育不良（BPD，一种早产儿的纤维化疾病）的病理生理学中起作用。对人新生儿肺组织进行的免疫组织化学染色显示，与死于先天性畸形的婴儿相比，死于肺炎或BPD的婴儿肺组织中TRAF1的表达增加。这些研究支持以下假说：TRAF1和cIAP2基因在肺细胞中受到高度调节，并且可能在人类肺部疾病中发挥作用。
