Blom W M, De Bont H J, Meijerman I, Kuppen P J, Mulder G J, Nagelkerke J F
Division of Toxicology, Leiden-Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
Hepatology. 1999 Mar;29(3):785-92. doi: 10.1002/hep.510290303.
Natural killer (NK) cells play a crucial role in the elimination of virus-infected or transformed cells in the liver. In this article, we describe the mechanism by which liver cells are killed by NK cells. Interleukin-2-activated natural killer (A-NK) cells from the rat induced apoptotic cell death in 30% of freshly isolated rat hepatocytes within 60 minutes. Recognition by the A-NK cells of the hepatocytes as nonself was established by masking the major histocompatibility complex (MHC) class I molecules on the hepatocytes with the OX18 antibody. During the killing process, a decrease of the mitochondrial membrane potential (MMP), formation of blebs, phosphatidyl serine (PS) externalization, chromatin condensation, and nuclear fragmentation were observed. The hepatocytes became apoptotic before permeabilization of the plasma membrane occurred, suggesting that the observed cytolysis was caused by secondary necrosis. The apoptotic process was completely abolished by the caspase inhibitors, Z-Val-Ala-DL-Asp fluormethylketone (zVAD-fmk) and Ac-Asp-Glu-Val-aldehyde (DEVD-cho). However, under these conditions, A-NK cells killed a smaller fraction of the hepatocytes by (primary) necrosis. These results indicate that apoptosis is the major cytotoxic process induced by A-NK cells in hepatocytes. If apoptosis is prevented, a more limited necrotic effect is induced. Therefore, this study shows that NK cells are fully equipped to induce both apoptosis and necrosis in hepatocytes, but appear to prefer the apoptotic route.
自然杀伤（NK）细胞在清除肝脏中病毒感染或转化的细胞方面发挥着关键作用。在本文中，我们描述了NK细胞杀死肝细胞的机制。来自大鼠的白细胞介素-2激活的自然杀伤（A-NK）细胞在60分钟内可诱导30%的新鲜分离的大鼠肝细胞发生凋亡性细胞死亡。通过用OX18抗体掩盖肝细胞上的主要组织相容性复合体（MHC）I类分子，确定了A-NK细胞将肝细胞识别为非自身细胞。在杀伤过程中，观察到线粒体膜电位（MMP）降低、形成泡状、磷脂酰丝氨酸（PS）外化、染色质凝聚和核碎裂。在质膜通透化之前，肝细胞就已发生凋亡，这表明观察到的细胞溶解是由继发性坏死引起的。半胱天冬酶抑制剂Z-Val-Ala-DL-Asp氟甲基酮（zVAD-fmk）和Ac-Asp-Glu-Val-醛（DEVD-cho）可完全消除凋亡过程。然而，在这些条件下，A-NK细胞通过（原发性）坏死杀死的肝细胞比例较小。这些结果表明，凋亡是A-NK细胞在肝细胞中诱导的主要细胞毒性过程。如果凋亡被阻止，则会诱导更有限的坏死效应。因此，本研究表明，NK细胞完全有能力在肝细胞中诱导凋亡和坏死，但似乎更倾向于凋亡途径。
