p38α MAPK inhibits JNK activation and collaborates with IκB 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 p38 alpha in mice results in excessive activation of JNK in the liver after in vivo challenge with bacterial lipopolysaccharide (LPS). Despite increased JNK activity, p38 alpha-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 p38 alpha and I kappa B kinase 2 (IKK2) in hepatocytes. Therefore, when combined with partial nuclear factor-kappa B inhibition, p38 alpha deficiency sensitizes the liver to cytokine-induced damage. Collectively, these results reveal a new function of p38 alpha in collaborating with IKK2 to protect the liver from LPS/TNF-induced failure by controlling JNK activation.