Modulation by caspases of tumor necrosis factor-stimulated c-Jun N-terminal kinase activation but not nuclear factor-kappaB signaling.
Tumour necrosis factor-alpha (TNF) is capable of activating many downstream signaling molecules via its two receptors TNFR1 and TNFR2. TNF can stimulate the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) as well as the stress induced kinase c-Jun N-terminal kinase (JNK) through mechanisms that are not fully delineated. NF-kappaB becomes activated mainly through TNFR1 while JNK can be stimulated by either TNF receptor subtype. TNF can also induce apoptosis within cells due to its ability to recruit procaspase-8 to TNFR1, which in turn induces the caspase proteolytic cascade. We provide evidence here in human cells, that TNF-induced JNK activation is under the influence of caspases while NF-kappaB activity is not. By using pharmacological inhibitors of caspases, we have shown that JNK activity is reduced following caspase inhibition, especially when caspase-3 is targeted. NF-kappaB activity, as assessed by IkappaBalpha or IkappaBbeta degradation, electrophoretic mobility shift assay and NF-kappaB gene reporter assays, is shown to be unaffected by caspase inhibition. Therefore, downstream TNF receptor signaling events are differentially influenced by caspases.
Littlejohn
Alison F
AF
Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland AB25 2ZD, UK.
Tucker
Steven J
SJ
Mohamed
Ahmed A A
AA
McKay
Stephen
S
Helms
Matt J
MJ
Vandenabeele
Peter
P
MacEwan
David J
DJ
D015703:Antigens, CD / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D015703:Antigens, CD; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases