title: Interleukin-1β enhances FasL-induced caspase-3/-7 activity without increasing apoptosis in primary mouse hepatocytes.
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.
authors.affiliation: Department of Pharmaceutical Biology and Biotechnology, Albert Ludwigs University Freiburg, Freiburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Lutz
authors.affiliation: Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Sanwald
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany.
authors.forename: Ronny
authors.initials: R
authors.lastname: Feuer
authors.affiliation: Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Sawodny
authors.affiliation: Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ederer
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert Ludwigs University Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, Freiburg, Germany; Bioss - Centre for Biological Signaling Studies, Albert Ludwigs University Freiburg, Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Borner
authors.affiliation: Department of Pharmaceutical Biology and Biotechnology, Albert Ludwigs University Freiburg, Freiburg, Germany.
authors.forename: Matjaz
authors.initials: M
authors.lastname: Humar
authors.affiliation: Department of Pharmaceutical Biology and Biotechnology, Albert Ludwigs University Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, Freiburg, Germany.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Merfort
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D053148:Caspase 3 / Q000378:metabolism*; D053179:Caspase 7 / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D053222:Fas Ligand Protein; D053583:Interleukin-1beta; D008565:Membrane Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053179:Caspase 7