Am. J. Respir. Cell Mol. Biol., Volume 26, Number 5, May, 2002 587-593

Production of Interleukin-6 by Skeletal Myotubes
Role of Reactive Oxygen Species

Ioanna Kosmidou, Theodoros Vassilakopoulos, Angeliki Xagorari, Spyros Zakynthinos, Andreas Papapetropoulos, and Charis Roussos

"George P. Livanos" Laboratory, Evangelismos Hospital, Department of Critical Care and Pulmonary Services, University of Athens, Athens, Greece

In the present study we have tested the ability of reactive oxygen species (ROS) to stimulate the production of interleukin (IL)- 6 from skeletal myocytes. Differentiated C2C12 murine skeletal muscle cells (myotubes) exposed to pyrogallol (PYR), xanthine/ xanthine-oxidase (X/XO), or H₂O₂ for 24 h exhibited a concentration-dependent increase in IL-6 production. Unlike myotubes, incubation of myoblasts and endothelial cells with X/XO or PYR did not result in increased IL-6 release. In myotubes, superoxide dismutase and catalase blocked the ROS-induced IL-6 release. Exposure of myotubes to H₂O₂ increased steady-state IL-6 mRNA levels, and pretreatment of myotubes with actinomycin D or cycloheximide abolished the ROS-induced IL-6 production. In addition, pretreatment of cells with N-acetyl-cysteine blocked tumor necrosis factor (TNF)--induced IL-6 release, suggesting that endogenously produced ROS participate in IL-6 production. Myotubes stimulated with H₂O₂ exhibited increased IB- phosphorylation and degradation, and treatment of C2C12 with ROS-generating agents increased activator protein (AP)-1 and nuclear factor (NF)-B-dependent promoter activity. Finally, preincubation of myotubes with the pharmacologic inhibitor of NF-B, diethyldithiocarbamate, or transient transfection with an IB- mutant, inhibited the ROS-stimulated IL-6 release. In conclusion, ROS stimulate IL-6 production from skeletal myotubes in a manner that involves transcriptional activation of the IL-6 gene through an NF-B-dependent pathway.

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