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Interleukin‐2–activated natural killer cells can induce both apoptosis and necrosis in rat hepatocytes
Author(s) -
Blom W. Marty,
De Bont Hans J. G. M.,
Meijerman Irma,
Kuppen Peter J. K.,
Mulder Gerard J.,
Nagelkerke J. Fred
Publication year - 1999
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510290303
Subject(s) - apoptosis , biology , microbiology and biotechnology , cytotoxic t cell , necrosis , natural killer cell , tumor necrosis factor alpha , cytolysis , interleukin 12 , lymphokine activated killer cell , natural killer t cell , immunology , biochemistry , in vitro , genetics
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.