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1 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.
Toll-like receptors (TLRs) comprise a critical sentinel that monitors body compartments for the presence of pathogens. Skeletal muscle expresses TLRs and responds to pathogen associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS), by mounting an innate immune
response. Although immune cells confront the bulk of infectious agents, skeletal muscle cells also possess both afferent and efferent limbs of the innate immune system. In the current study we used C2C12 myocytes as a model system for skeletal muscle during infection. C2C12 cells
responded to LPS in a time frame and with a pattern of gene expression that faithfully mimicked the response of skeletal muscle to LPS in vivo. LPS from a variety of E. coli serotypes stimulated interleukin (IL)-6 synthesis. C2C12 cells expressed TLR1-7 mRNA, but not TLR-8 or -9 by RTPCR. A synthetic tri-palmityolated cysteine, serine, lysine containing peptide (Pam) and LPS from Porphyromonas gingivalis, two TLR2 ligands, also stimulated IL-6 expression. Poly inosinic-polycytidylic acid (Poly I:C), a double stranded RNA mimetic and TLR3 ligand failed to stimulate IL-6 synthesis. Both LPS and Pam stimulated luciferase activity driven from NF
B and IL-6 promoter containing plasmids, and this response was blunted when the NFB binding site in the IL-6 promoter was mutated. LPS- and Pam-stimulated IL-6 expression were inhibited by the proteasome inhibitor MG132, the IKK2 inhibitor TPCA-1, and the anti-inflammatory glucocorticoid dexamethasone. Pam-stimulated NFB and IL-6 promoter activit ies were disrupted by a dominant negative form of TLR2, but not TLR4. Local injection of LPS or Pam into the gastrocnemius muscle stimulated IL-6 mRNA expression in the injected but not in the contralateral muscle. The LPS- but not Pam-stimulated expression of IL-6 mRNA was blunted in skeletal muscle from C3H/HeJ mice carrying an inactivating mutation in TLR4 when compared to syngeneic C3H/SnJ mice. The data suggest that skeletal muscle in general and muscle cells in particular recognize pathogen associated molecules with specific TLRs. These receptors initiate an IL-6 transcriptional response whose specific signaling components are shared between the two TLRs.
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