Irradiation leads to sensitization of hepatocytes to TNF-α-mediated apoptosis by upregulation of IκB expression

Abstract

This study aimed to reveal the pathophysiological signalling responsible for radiation-induced sensitization of hepatocytes to TNF--mediated apoptosis. I B was upregulated in irradiated hepatocytes. Administration of I B antisense oligonucleotides prior to irradiation inhibited occurrence of apoptosis after TNF-administration. Caspases-8, -9 and -3 activities were increased in irradiated hepatocytes and downregulation of apoptosis by I B antisense oligonucleotides was mediated by suppression of caspases-9 and -3 activation but not of caspase-8 activation, suggesting that radiation-induced sensitization of hepatocytes to TNF--mediated apoptosis additionally requires changes upstream of caspase-8 activation. Herein, upregulation of FLIP may play a crucial role. Cleavage of bid, upregulation of bax, downregulation of bcl-2 and release of cytochrome c after TNF--administration depend on radiation-induced upregulation of I B, thus demonstrating an apoptosis permitting eVect of I B.

The impact of mouse strain on iron ion radio-immune response of leukocyte populations

“…In contrast, temporarily blocking apoptosis (e.g., via caspase-inhibitors), may eliminate straindependent differences without reducing the radiation effect. Caspases 8 and 9 appear to be particularly promising targets as they have already been implicated in radiation-induced apoptosis in rat hepatocytes (Gurleyen et al 2009). As the primary difference between these two strains in terms of their radiation response seems to involve susceptibility to apoptosis, normalisation of apoptosis should eliminate the straindependent dose responses.…”

Effect of tumour necrosis factor‐α and irradiation alone or in combination on the viability of hepatocellular and biliary adenocarcinoma cell lines in vitro

“…Cells were irradiated with 6 MV photons at a dose rate of 2.4 Gy/min using a Varian Clinac 600 C accelerator (Varian, Palo Alto, CA, USA) as described previously (26–28, 34, 35, 38). Radiation doses of 2, 4, 8 and 25 Gy were applied.…”

“…Our data revealed that the pro‐inflammatory cytokine TNF‐α is of particular interest in the processes taking place after liver irradiation as radiation causes hepatocytes to become susceptible to TNF‐α‐mediated apoptosis (35). Therefore, radiation‐induced apoptosis of liver macrophages, Kupffer cells, may lead to a release of TNF‐α in the microenvironment (35) followed by apoptosis of the irradiated hepatocytes by radiation‐induced upregulation of IκB expression (38).…”

“…Therefore, the aim of the present study was to evaluate the influence of TNF‐α and radiation alone or in combination on the viability of several hepatocellular and biliary tumour cells in vitro . Furthermore, radiation‐induced changes of TNF‐α, TNF receptors 1 and 2 as well as IκB expression were evaluated to elucidate the intracellular mechanisms and the possible differences in the radiation‐induced changes in hepatocytes in which the pro‐apoptotic effect of TNF‐α after irradiation requires radiation‐induced upregulation of IκB expression (38).…”

In Regard to “Radiation-Induced Liver Fibrosis is Mitigated by Gene Therapy Inhibiting Transforming Growth Factor-β Signalling in the Rat” by Shi-Suo Du et al. (Int J Radiat Oncol Biol Phys 2010;78:1513–1523)

“…However, TGF-b was not upregulated to such an extent in our model within the first 48 hours after irradiation (maximum threefold). Radiation-induced cytokine expression, on the one hand, influences cell viability of hepatocytes because in vitro experiments have shown that irradiation leads to susceptibility of hepatocytes to TNF-alpha mediated apoptosis (5,6). On the other hand, radiation-induced cytokine expression also influences gene expression (4,7,8), and liver metabolism as has been shown exemplary for disturbed iron metabolism after liver irradiation (7).…”