The JNK MAP kinase pathway contributes to the development of endotoxin-induced diaphragm caspase activation

Gerald S. Supinski, Xinying Ji, Leigh Ann Callahan

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

We previously demonstrated that endotoxin-induced sepsis results in caspase 8-mediated diaphragmatic dysfunction. The upstream signaling pathways modulating diaphragm caspase 8 activation in response to endotoxin administration are, however, unknown. The purpose of the present study was to test the hypothesis that the JNK (Jun N-terminal Kinase) pathway is activated in the diaphragm during sepsis and contributes to sepsis-induced diaphragm caspase 8 activation. Endotoxin was administered to intact animals to model the effects of sepsis. We first assessed the time course of JNK activation after endotoxin (12 mg/kg ip) administration to mice. We then determined whether JNK inhibitor administration ( 30 μm/kg ip SP600125) could prevent caspase 8 activation and diaphragm weakness in endotoxin-treated mice. Experiments were then repeated comparing the effects of endotoxin on control and transgenic JNK knockout mice. We finally determined whether cytomix (LPS, TNFα, IL1β, and IFN-γ) exposure activated caspase 8 in C2C12 muscle cells and whether caspase 8 activation was attenuated by either chemical inhibition of JNK (30 μM SP600125) or transfection with a dominant negative JNK construct. We found that endotoxin activated diaphragm JNK (P < 0.001) and increased active caspase 8 (P < 0.01). Inhibition of JNK with SP600125 or by use of JNK-deficient animals prevented diaphragm caspase 8 activation (P < 0.01) and prevented diaphragm weakness (P < 0.05). JNK inhibition also prevented caspase 8 activation in cytokine-treated muscle cells (P < 0.001). These data implicate JNK activation as a major factor mediating inflammation-induced skeletal muscle caspase 8 activation and weakness.

Original languageEnglish
Pages (from-to)R825-R834
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume297
Issue number3
DOIs
StatePublished - Sep 2009

Keywords

  • Endotoxin
  • Proteolysis

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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