HBSAG RETENTION SENSITIZES THE HEPATOCYTE TO INJURY BY PHYSIOLOGICAL CONCENTRATIONS OF INTERFERON-GAMMA
HBSAG RETENTION SENSITIZES THE HEPATOCYTE TO INJURY BY PHYSIOLOGICAL CONCENTRATIONS OF INTERFERON-GAMMA
复制标题
DOI：
10.1002/hep.1840160308
复制
发表时间：
1992-09-01
期刊：
影响因子：
13.5
通讯作者：
CHISARI, FV
中科院分区：
文献类型：
--
作者：
GILLES, PN;GUERRETTE, DL;CHISARI, FV
炎性细胞因子在乙肝病毒的生命周期及其相关肝病的发病机制中可能发挥的作用尚未被仔细描述。在这份报告中，我们证明了细菌脂多糖，一种有效的体内炎性细胞因子的诱导剂，在转基因小鼠中引起严重的急性肝病，转基因小鼠的肝细胞产生乙肝病毒大包膜多肽并将HBs Ag保留在内质网中。相比之下，100倍高剂量的细菌脂多糖不会在非转基因对照鼠或肝细胞分泌而不是保留乙肝表面抗原的转基因小鼠中引起肝细胞损伤。与肝细胞损伤和炎症细胞进入肝脏相一致，肝内乙肝病毒稳态信使RNA含量显著减少，从而证实了这一过程对HBs Ag阳性肝细胞的选择性。细菌脂多糖诱导的肝细胞损伤似乎主要是由干扰素-γ介导的，因为预先给予中和干扰素-γ的单抗可以显著减轻这种损伤，而且重组干扰素-γ对体内HBs Ag阳性的转基因肝细胞也具有选择性的细胞毒作用。肿瘤坏死因子-α也参与了这一过程，因为肿瘤坏死因子-α特异性单抗可以显著减轻细菌脂多糖诱导的肝细胞损伤。然而，肿瘤坏死因子-α在细菌脂多糖诱导的肝细胞损伤中的作用不如干扰素-γ清楚，因为与干扰素-γ不同的是，它对非转基因肝细胞也是有毒的。这些结果表明，转基因小鼠肝细胞对干扰素-γ在体内的破坏是选择性敏感的。由于这种细胞因子已被证明是在人类病毒性肝炎期间由肝内淋巴细胞产生的，这些结果提出了一种可能性，即类似的途径可能有助于清除HBs Ag阳性的肝细胞，并在人类乙肝病毒感染的肝细胞损伤的发病机制中起作用。
The role that inflammatory cytokines may play in the life cycle of the hepatitis B virus and in the pathogenesis of its associated liver disease has not been carefully delineated. In this report, we demonstrate that bacterial lipopolysaccharide, a potent inducer of inflammatory cytokines in vivo, causes a severe acute liver disease in transgenic mice whose hepatocytes produce the hepatitis B virus large envelope polypeptide and retain HBsAg within the endoplasmic reticulum. In contrast, 100-fold higher doses of bacterial lipopolysaccharide do not induce liver cell injury in nontransgenic littermate controls or in transgenic mice whose hepatocytes secrete HBsAg rather than retain it. Coincident with the hepatocellular injury and the influx of inflammatory cells into the liver, a marked reduction occurs in the intrahepatic content of hepatitis B virus steady-state messenger RNA, thereby confirming the selectivity of this process for the HBsAg-positive hepatocyte. Bacterial lipopolysaccharide-induced hepatocellular injury appears to be principally mediated by interferon-gamma because it can be markedly reduced by the prior administration of neutralizing interferon-gamma-specific monoclonal antibodies and because recombinant interferon-gamma is also selectively cytotoxic for the HBsAg-positive transgenic hepatocyte in vivo. Tumor necrosis factor-alpha is also involved in this process because bacterial lipopolysaccharide-induced liver cell injury is significantly reduced by tumor necrosis factor-alpha specific monoclonal antibodies. The role of tumor necrosis factor-alpha in bacterial lipopolysaccharide-induced liver cell injury is less clear than interferon-gamma, however, because unlike interferon-gamma it is also toxic for nontransgenic hepatocytes. These results demonstrate that the HBsAg-positive transgenic mouse hepatocyte is selectively sensitive to destruction by interferon-gamma in vivo. Because this cytokine has been shown to be produced by intrahepatic lymphocytes during viral hepatitis in humans, these results raise the possibility that a similar pathway may contribute to the clearance of HBsAg-positive hepatocytes and to the pathogenesis of liver cell injury in human HBV infection as well.