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Articles in PresS, published online ahead of print June 6, 2002
Am J Physiol Regu Physiol, 10.1152/ajpregu.00039.2002
Submitted on January 22, 2002
Accepted on May 30, 2002
1 Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA, USA
* To whom correspondence should be addressed. E-mail: rfrost{at}psu.edu.
The purpose of the present study was to examine the regulation of tumor necrosis factor
(TNF
) and interleukin (IL)-6 by lipopolysaccharide (LPS) in C2C12 myoblasts and mouse skeletal muscle. LPS produced dose- and time-dependent increases in TNF
and IL-6 mRNA content in C2C12 myoblasts. The LPS-induced cytokine response could be mimicked by peptidoglycan from the cell wall of Staphylococcus aureus but not by zymosan A, a cell wall component from Saccharomyces cerevisiae. Ongoing protein synthesis was not necessary for the increase in the two cytokine mRNAs. The transcriptional inhibitor DRB blocked LPS-stimulated IL-6 mRNA expression without changing mRNA half-life. The anti-inflammatory glucocorticoid dexamethasone selectively blocked LPS-stimulated IL-6 mRNA accumulation, but not TNF
. In contrast, the proteasomal inhibitor MG132 blocked TNF
mRNA expression, but not IL-6. Exposure of myoblasts to LPS was associated with a rapid decrease in the inhibitor of nuclear factor kappa B (I kappa B
, and
) and this response was also blocked by MG132. Treatment of myocytes with IL-1 or TNF
also increased IL-6 mRNA content, but the increase in IL-6 mRNA due to LPS could not be prevented by pretreatment with antagonist to either IL-1 or TNF. Under in vivo conditions, LPS increased the plasma concentration of TNF
and IL-6 and stimulated the accumulation of their mRNAs in multiple tissues including skeletal muscle from wild-type mice. In contrast, the ability of LPS to stimulate the same cytokines was markedly decreased in mice that harbor a mutation in the toll-like receptor 4. Our data suggest that LPS stimulates cytokine expression not only in classical immune tissues, but also in skeletal muscle.
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