p38 alpha MAPK inhibits JNK activation and collaborates with IkappaB kinase 2 to prevent endotoxin-induced liver failure |
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Authors: | Heinrichsdorff Jan Luedde Tom Perdiguero Eusebio Nebreda Angel R Pasparakis Manolis |
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Institution: | Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47, D-50674 Cologne, Germany. |
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Abstract: | Activation of c-Jun amino-terminal kinase (JNK) facilitates tumour necrosis factor (TNF)-induced cell death. The p38 mitogen-activated protein kinase pathway is induced by TNF stimulation, but it has not been implicated in TNF-induced cell death. Here, we show that hepatocyte-specific ablation of p38alpha in mice results in excessive activation of JNK in the liver after in vivo challenge with bacterial lipopolysaccharide (LPS). Despite increased JNK activity, p38alpha-deficient hepatocytes were not sensitive to LPS/TNF toxicity showing that JNK activation was not sufficient to mediate TNF-induced liver damage. By contrast, LPS injection caused liver failure in mice lacking both p38alpha and IkappaB kinase 2 (IKK2) in hepatocytes. Therefore, when combined with partial nuclear factor-kappaB inhibition, p38alpha deficiency sensitizes the liver to cytokine-induced damage. Collectively, these results reveal a new function of p38alpha in collaborating with IKK2 to protect the liver from LPS/TNF-induced failure by controlling JNK activation. |
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Keywords: | cytokine signalling liver failure p38 JNK NF-κB |
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