HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/R825    most recent 90849.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Supinski, G. S. Articles by Callahan, L. A. PubMed PubMed Citation Articles by Supinski, G. S. Articles by Callahan, L. A.

ARTICLES

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

Division of Pulmonary, Critical Care and Sleep Medicine, University of Kentucky, Lexington, Kentucky

Submitted 21 October 2008 ; accepted in final form 6 July 2009

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, TNF, IL1β, and IFN-) 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.

endotoxin; proteolysis