p38 alpha MAPK inhibits JNK activation and collaborates with IkappaB kinase 2 to prevent endotoxin-induced liver failure.
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.
Heinrichsdorff
Jan
J
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.
Luedde
Tom
T
Perdiguero
Eusebio
E
Nebreda
Angel R
AR
Pasparakis
Manolis
M
D000818:Animals; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004789:Enzyme Activation / Q000502:physiology; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D017093:Liver Failure / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D004731:Endotoxins; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases