Abstract
Sustained inflammation may increase the susceptibility of hepatocytes to apoptotic cell death and therefore exacerbate liver damage. Here we report that the pro-inflammatory cytokine IL-1β sensitizes primary murine hepatocytes to Fas ligand (FasL)-induced caspase-3/-7 activity. This process was dependent on JNK1/2 and the BH3-only proteins Bim and Bid. Mathematical modeling revealed that incubation of hepatocytes with IL-1β depleted the anti-apoptotic Bcl-2 protein pool and thus shifted hepatocytes to mitochondrial type II apoptosis following Fas activation. As a consequence, IL-1β and FasL treatment enhanced cytochrome c release. Surprisingly, despite increased caspase-3/-7 activation, FasL-induced cell death was reduced by IL-1β pre-treatment. This protective effect was independent of JNK1/2, Bim or Bid. Furthermore, elevated caspase-3/-7 activity upon IL-1β and FasL treatment did not result in enhanced PARP cleavage. The protective effect of IL-1β was seen after 3 h of pre-incubation, indicating an anti-apoptotic transcriptional response. Indeed, NF-κB DNA binding was increased in response to IL-1β plus FasL and gene-expression profiling of NF-κB regulated genes revealed a transcriptional and translational upregulation of the caspase-8 inhibitor A20. A mathematical model was developed to explain the contradictious occurrence of both increased caspase-3/-7 activity and elevated cell viability by including a heterogeneous distribution of Bcl-2 proteins and variations in Fas signaling resulting in different subpopulations of hepatocytes.
Highlights
Hepatocyte apoptosis is critically involved in the pathogenesis of liver diseases and inflammation and is regarded as one of the driving forces of cirrhosis, the final stage of chronic liver disease
The maintenance of liver homeostasis is procured by different cytokines such as tumor necrosis factor a (TNFa), interleukin-6 (IL-6), and interleukin-1b (IL-1b), which mediate signaling between the different cell types of the liver organ [1]
Similar to the TNFa/Fas ligand (FasL) sensitization, we noted a clear increase in caspase-3/-7 activity in cells treated with IL-1b and FasL as compared to those treated with FasL alone (Fig. 1A)
Summary
Hepatocyte apoptosis is critically involved in the pathogenesis of liver diseases and inflammation and is regarded as one of the driving forces of cirrhosis, the final stage of chronic liver disease. An in-depth understanding of the mechanistic interplay of different soluble and cell-associated apoptotic and pro-inflammatory signals is urgently needed. The maintenance of liver homeostasis is procured by different cytokines such as tumor necrosis factor a (TNFa), interleukin-6 (IL-6), and interleukin-1b (IL-1b), which mediate signaling between the different cell types of the liver organ [1]. In a previous study we showed that pre-incubation with TNFa sensitizes primary murine hepatocytes to Fas ligand (FasL) induced apoptosis [2]. It was reported that IL-1b protects mice from FasL-induced apoptosis [3], but negatively influenced liver disease [4, 5]. Binding to its cell surface interleukin-1 receptor (IL-1R) [6] results in the activation of different signaling pathways, including those governed by c-Jun, p38-MAPK or NF-kB [7, 8]
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