Upregulation of tumor necrosis factor-alpha gene by Epstein-Barr virus and activation of macrophages in Epstein-Barr virus-infected T cells in the pathogenesis of hemophagocytic syndrome
Upregulation of tumor necrosis factor-alpha gene by Epstein-Barr virus and activation of macrophages in Epstein-Barr virus-infected T cells in the pathogenesis of hemophagocytic syndrome
复制标题
DOI：
10.1172/jci119728
复制
发表时间：
1997-10-15
影响因子：
15.9
通讯作者：
Su, IJ
中科院分区：
文献类型：
--
作者：
Lay, JD;Tsao, CJ;Su, IJ
在恶性淋巴瘤患者中，特别是在EBV感染的T细胞淋巴瘤中，已经注意到潜在致命的噬血细胞综合征。细胞因子，如干扰素-γ（IFN-γ）、TNF-α和IL-1 α在患者血清中升高。为了验证EBV感染T细胞是否会上调特异性细胞因子基因并随后激活巨噬细胞导致噬血细胞综合征，我们研究了EBV感染和EBV阴性淋巴瘤组织中TNF-α、IFN-γ和IL-1 α的转录本。通过逆转录PCR分析，在14例EBV感染的T细胞淋巴瘤中有8例（57%）检测到TNF-α的转录本，高于EBV阴性T细胞淋巴瘤（6例中的1例，17%）、EBV阳性B细胞淋巴瘤（5例中的2例，40%）和EBV阴性B细胞淋巴瘤（7例中的1例，14%）。IFN-γ的转录物在T细胞淋巴瘤中一致地检测到，偶尔在B细胞淋巴瘤中检测到，但与EBV状态无关。在任何类别中均未检测到IL-1 α表达。与这些体内观察结果一致，T细胞淋巴瘤系的体外EBV感染引起TNF-α基因的上调，并增加TNF-α的分泌，而不是IFN-γ或IL-1 α。EBV感染B细胞淋巴瘤细胞系，TNF-α、IFN-γ和IL-1 α的表达没有改变。为了鉴定负责巨噬细胞活化的特异性细胞因子，将来自EBV感染的T细胞的培养上清液与单核细胞系U937共培养24小时。观察到U937细胞增强的吞噬作用和TNF-α、IFN-γ和IL-1 α的分泌，并且可以在很大程度上被抗TNF-α（70%）抑制，被抗IFN-γ（31%）抑制效果较低，但几乎完全被抗TNF-α和抗IFN-γ的组合（85%）抑制。总之，体内和体外观察结果表明，EBV感染T细胞选择性上调TNF-α表达，其与IFN-γ和可能的其他细胞因子组合可激活巨噬细胞。这项研究不仅强调了病毒相关噬血细胞综合征的可能发病机制，而且还表明抗TNF-α在其致命综合征的背景下具有治疗潜力。
A potentially fatal hemophagocytic syndrome has been noted in patients with malignant lymphomas, particularly in EBV-infected T cell lymphoma, Cytokines, such as interferon-gamma (IFN-gamma), TNF-alpha, and IL-1 alpha, are elevated in patients' sera. To verify whether infection of T cells by EBV will upregulate specific cytokine genes and subsequently activate macrophages leading to hemophagocytic syndrome, we studied the transcripts of TNF-alpha, IFN-gamma, and IL-1 alpha in EBV-infected and EBV-negative lymphoma tissues, By reverse transcription PCR analysis, transcripts of TNF-alpha were detected in 8 (57%) of 14 EBV-infected T cell lymphomas, higher than that detected in EBV-negative T cell lymphoma (one of six, 17%), EBV-positive B cell lymphoma (two of five, 40%) and EBV-negative B cell lymphomas (one of seven, 14%). Transcripts of IFN-gamma were consistently detected in T cell lymphoma and occasionally in B cell lymphoma, but were independent of EBV status. IL-1 alpha expression was not detectable in any category. Consistent with these in vivo observations, in vitro EBV infection of T cell lymphoma lines caused upregulation of TNF-alpha gene, and increased secretion of TNF-alpha, but not IFN-gamma or IL-1 alpha. Expression of TNF-alpha, IFN-gamma, and IL-1 alpha was not changed by EBV infection of B cell lymphoma lines. To identify the specific cytokine(s) responsible for macrophage activation, culture supernatants from EBV-infected T cells were cocultured with a monocytic cell line U937 for 24 h. Enhanced phagocytosis and secretion of TNF-alpha, IFN-gamma, and IL-1 alpha by U937 cells were observed, and could be inhibited to a large extent by anti-TNF-alpha (70%), less effectively by anti-IFN-gamma (31%), but almost completely by the combination of anti-TNF-alpha and anti-IFN-gamma (85%). Taken together, the in vivo and in vitro observations suggest that infection of T cells by EBV selectively upregulates the TNF-alpha expression which, in combination with IFN-gamma and probably other cytokines, can activate macrophages. This study not only highlights a probable pathogenesis for virus-associated hemophagocytic syndrome, but also suggests that anti-TNF-alpha will have therapeutic potential in the context of their fatal syndrome.