Cytokine regulation of pro- and anti-apoptotic genes in rat hepatocytes: NF-kappa B-regulated inhibitor of apoptosis protein 2 (cIAP2) prevents apoptosis

MH Schoemaker*, Jenny Kootstra-Ros, M Homan, C Trautwein, P Liston, K Poelstra, H van Goor, PLM Jansen, H Moshage

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background/Aims: In acute liver failure, hepatocytes are exposed to various cytokines that activate both cell survival and apoptotic pathways. NF-kappaB is a central transcription factor in these responses. Recent studies indicate that blocking NF-kappaB causes apoptosis, indicating the existence of NF-kappaB-regulated anti-apoptotic genes. In the present study the relationship between NF-kappaB activation and apoptosis has been investigated in hepatocytes.

Methods: Primary rat hepatocytes were exposed to a cytokine mixture of tumor necrosis factor alpha, interleukin-1beta, interferon-gamma and lipopolysaccharide. Modulation of signalling pathways was performed by using dominant negative adenoviral constructs. Apoptosis and NF-kappaB activation were determined by caspase-3 activity, Hoechst staining and electrophoretic mobility shift assay, respectively. Furthermore, expression and regulation of apoptosis-related genes were investigated.

Results: (1) Inhibition of NF-kappaB activation results in apoptosis. (2) Inhibitor of apoptosis protein (IAP) family members, inhibitor of apoptosis protein1 (cIAP1), and X-chromosome-linked IAP, are expressed in rat hepatocytes. cIAP2 is induced by cytokines in an NF-kappaB-dependent manner and overexpression of cIAP2 inhibits apoptosis. (3) The anti-apoptotic Bcl-2 family member A1/Bfl-1 and the pro-apoptotic members Bak and Bid are induced by cytokines and NF-kappaB-dependent. (4) Nitric oxide inhibits caspase-3 activity in hepatocytes.

Conclusions: In inflammatory conditions, hepatocyte survival is dependent on NF-kappaB activation and cIAP2 contributes significantly to this protection.

(C) 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.

Original languageEnglish
Article numberPII S0168-8278(02)00063-6
Pages (from-to)742-750
Number of pages9
JournalJournal of Hepatology
Volume36
Issue number6
Publication statusPublished - Jun-2002
Event51st Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease -
Duration: 27-Oct-20001-Nov-2000

Keywords

  • inflammation
  • apoptosis
  • NT-KB
  • adenovirus
  • inhibitor of apoptosis protein family
  • bcl-2 family
  • nitric oxide
  • NECROSIS-FACTOR-ALPHA
  • MITOCHONDRIAL PERMEABILITY TRANSITION
  • NITRIC-OXIDE SYNTHASE
  • IAP FAMILY PROTEINS
  • CELL-DEATH
  • ENDOTHELIAL-CELLS
  • BCL-2 FAMILY
  • IN-VIVO
  • LIVER
  • EXPRESSION

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