Spengler U, Zachoval R, Gallati H, Jung M C, Hoffmann R, Riethmüller G, Pape G
Department of General Internal Medicine, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany.
Cytokine. 1996 Nov;8(11):864-72. doi: 10.1006/cyto.1996.0115.
Cells respond to tumour necrosis factor-alpha (TNF-alpha) via binding to 75-kDa (type A) and 55-kDa (type B) receptors which have different intracellular signalling pathways and can also circulate as soluble molecules. Both receptors are co-expressed in many tissues, but their relative contributions to cellular TNF responses is for most situations unknown. In patients with viral and non-viral inflammatory liver diseases serum TNF-alpha was determined by an immunoenzymetric assay and soluble type A and B TNF receptors (TNF-alpha r) by enzyme-linked immunological and biological assays (ELIBA). In addition, cellular expression of TNF and its binding proteins were studied in liver biopsies by an indirect immunoperoxidase technique. Secretion of TNF-alpha and upregulation of TNF-alpha r-A were particularly prominent in viral hepatitis. Strong TNF-alpha in-situ production by mononuclear cells could be demonstrated in liver biopsies from patients with acute viral hepatitis. However, TNF-alpha r-A was detected only on hepatocytes. Serum TNF-alpha r-A was elevated two-fold in relative abundance over TNF-alpha r-B and was correlated to serum TNF-alpha (r = 0.6464, P < 0.0001). Soluble TNF-alpha r levels normalized, when the viral hepatitis was cleared, and successful therapy of hepatitis B was associated with a temporary rise of TNF-alpha r-A during the initial flare of aminotransferase. Patients with alcoholic hepatitis had also evidence of TNF-alpha activation but clearly differed from patients with viral induced liver diseases: Soluble TNF-alpha r-A and TNF-alpha r-B were highly elevated in equal proportions. In situ analysis in liver biopsies revealed a distinctive pattern of TNF-alpha r expression with strong cytoplasmic staining for both TNF-alpha r-A and B on scattered hepatocytes in addition to infiltrating mononuclear cells. The data propose that TNF release during antiviral immune responses is predominantly associated with TNF-alpha r-A upregulation and shedding, whereas upregulation and shedding of TNF-alpha r-B is more prominent in alcoholic hepatitis. As cytotoxicity and apoptosis by TNF are mediated mainly via TNF-alpha r-B, our results are consistent with more severe TNF-alpha induced liver damage in alcoholic hepatitis as compared to viral hepatitis.
细胞通过与75 kDa（A型）和55 kDa（B型）受体结合来对肿瘤坏死因子-α（TNF-α）作出反应，这两种受体具有不同的细胞内信号传导途径，并且也可以作为可溶性分子循环。两种受体在许多组织中共同表达，但在大多数情况下，它们对细胞TNF反应的相对贡献尚不清楚。在患有病毒性和非病毒性炎症性肝病的患者中，通过免疫酶测定法测定血清TNF-α，通过酶联免疫和生物学测定法（ELIBA）测定可溶性A型和B型TNF受体（TNF-α r）。此外，通过间接免疫过氧化物酶技术在肝活检中研究了TNF及其结合蛋白的细胞表达。TNF-α的分泌和TNF-α r-A的上调在病毒性肝炎中尤为突出。在急性病毒性肝炎患者的肝活检中可以证实单核细胞有强烈的TNF-α原位产生。然而，仅在肝细胞上检测到TNF-α r-A。血清TNF-α r-A的相对丰度比TNF-α r-B升高了两倍，并且与血清TNF-α相关（r = 0.6464，P <0.0001）。当病毒性肝炎清除时，可溶性TNF-α r水平恢复正常，并且乙型肝炎的成功治疗与转氨酶最初发作期间TNF-α r-A的暂时升高有关。酒精性肝炎患者也有TNF-α激活的证据，但明显不同于病毒性肝病患者：可溶性TNF-α r-A和TNF-α r-B以相等的比例高度升高。肝活检的原位分析显示了TNF-α r表达的独特模式，除了浸润的单核细胞外，在散在的肝细胞上，TNF-α r-A和B均有强烈的细胞质染色。数据表明，抗病毒免疫反应期间的TNF释放主要与TNF-α r-A的上调和脱落有关，而TNF-α r-B的上调和脱落在酒精性肝炎中更为突出。由于TNF的细胞毒性和凋亡主要通过TNF-α r-B介导，我们的结果与酒精性肝炎中与病毒性肝炎相比更严重的TNF-α诱导的肝损伤一致。
