TY - JOUR
T1 - Inhibition of JNK activation through NF-κB target genes
AU - Tang, Guilin
AU - Minemoto, Yuzuru
AU - Dibling, Benjamin
AU - Purcell, Nicole H.
AU - Li, Zhiwei
AU - Karin, Michael
AU - Lin, Anning
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 2001/11/15
Y1 - 2001/11/15
N2 - The proinflammatory cytokine tumour necrosis factor-α (TNF-α) regulates immune responses, inflammation and programmed cell death (apoptosis). The ultimate fate of a cell exposed to TNF-α is determined by signal integration between its different effectors, including IκB kinase (IKK), c-Jun N-terminal protein kinase (JNK) and caspases. Activation of caspases is required for apoptotic cell death, whereas IKK activation inhibits apoptosis through the transcription factor NF-κB, whose target genes include caspase inhibitors. JNK activates the transcription factor c-Jun/AP-1, as well as other targets. However, the role of JNK activation in apoptosis induced by TNF-α is less clear. It is unknown whether any crosstalk occurs between IKK and JNK, and, if so, how it affects TNF-α-induced apoptosis. We investigated this using murine embryonic fibroblasts that are deficient in either the IKKβ catalytic subunit of the IKK complex or the ReIA/p65 subunit of NF-κB. Here we show that in addition to inhibiting caspases, the IKK/NF-κB pathway negatively modulates TNF-α-mediated JNK activation, partly through NF-κB-induced X-chromosome-linked inhibitor of apoptosis (XIAP). This negative crosstalk, which is specific to TNF-α signalling and does not affect JNK activation by interleukin-1 (IL-1), contributes to inhibition of apoptosis.
AB - The proinflammatory cytokine tumour necrosis factor-α (TNF-α) regulates immune responses, inflammation and programmed cell death (apoptosis). The ultimate fate of a cell exposed to TNF-α is determined by signal integration between its different effectors, including IκB kinase (IKK), c-Jun N-terminal protein kinase (JNK) and caspases. Activation of caspases is required for apoptotic cell death, whereas IKK activation inhibits apoptosis through the transcription factor NF-κB, whose target genes include caspase inhibitors. JNK activates the transcription factor c-Jun/AP-1, as well as other targets. However, the role of JNK activation in apoptosis induced by TNF-α is less clear. It is unknown whether any crosstalk occurs between IKK and JNK, and, if so, how it affects TNF-α-induced apoptosis. We investigated this using murine embryonic fibroblasts that are deficient in either the IKKβ catalytic subunit of the IKK complex or the ReIA/p65 subunit of NF-κB. Here we show that in addition to inhibiting caspases, the IKK/NF-κB pathway negatively modulates TNF-α-mediated JNK activation, partly through NF-κB-induced X-chromosome-linked inhibitor of apoptosis (XIAP). This negative crosstalk, which is specific to TNF-α signalling and does not affect JNK activation by interleukin-1 (IL-1), contributes to inhibition of apoptosis.
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U2 - 10.1038/35104568
DO - 10.1038/35104568
M3 - Article
C2 - 11713531
AN - SCOPUS:0035891320
SN - 0028-0836
VL - 414
SP - 313
EP - 317
JO - Nature
JF - Nature
IS - 6861
ER -