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.
|Article number||PII S0168-8278(02)00063-6|
|Number of pages||9|
|Journal||Journal of Hepatology|
|Publication status||Published - Jun-2002|
|Event||51st Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease - |
Duration: 27-Oct-2000 → 1-Nov-2000
- inhibitor of apoptosis protein family
- bcl-2 family
- nitric oxide
- MITOCHONDRIAL PERMEABILITY TRANSITION
- NITRIC-OXIDE SYNTHASE
- IAP FAMILY PROTEINS
- BCL-2 FAMILY