Mechanisms of crosstalk between TNF-induced NF-kappaB and JNK activation in hepatocytes.
Hepatocyte cell death is a universal feature of inflammatory liver diseases. The observation that mice deficient in the activation of nuclear factor-kappaB (NF-kappaB) are not viable because of excessive hepatocyte apoptosis induced by tumor necrosis factor (TNF) made it crystal-clear that NF-kappaB plays a central role in protecting hepatocytes against TNF-induced cell death. Also during TNF-mediated liver injury, NF-kappaB was shown to have an essential anti-apoptotic effect, underscoring the therapeutic importance of understanding its underlying molecular mechanisms. For a long time, the ability of NF-kappaB to induce the expression of a variety of anti-apoptotic proteins was thought to be solely responsible for its cytoprotective effects. However, during the past few years it has become clear that NF-kappaB-mediated inhibition of cell death also involves attenuating TNF-induced activation of c-Jun activating kinase (JNK). Whereas transient activation of JNK upon TNF treatment is associated with cellular survival, prolonged JNK activation contributes to cell death. Several studies have shown that NF-kappaB activation inhibits the sustained phase of TNF-induced JNK activation and thus protects cells against TNF cytotoxicity. In this review, we will discuss the various mechanisms by which NF-kappaB activation blunts TNF-induced JNK activation, including the induction of JNK inhibitory proteins and controlling the levels of reactive oxygen species (ROS). Moreover, because the cytoprotective effects of NF-kappaB activation are particularly important in liver physiology, we will put each of these JNK-inhibitory mechanisms into a 'hepatic perspective' by discussing their role in various mouse models of TNF-mediated liver injury.
Wullaert
Andy
A
Unit for Molecular Signal Transduction in Inflammation, Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology (VIB), Ghent University, Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium.
Heyninck
Karen
K
Beyaert
Rudi
R
D000818:Animals; D016923:Cell Death / Q000502:physiology; D019610:Cytoprotection / Q000502:physiology; D022781:Hepatocytes / Q000201:enzymology* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases