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Peptidoglycan induces interleukin-6 expression through the TLR2 receptor, JNK, c-Jun, and AP-1 pathways in microglia

Hsiao-Yun Lin1, Chih-Hsin Tang, Jia-Hong Chen

  • 1Institute of Medical Science, China Medical University, Taichung, Taiwan.

Journal of Cellular Physiology
|October 15, 2010
PubMed

Insights

Peptidoglycan (PGN) from Gram-positive bacteria activates microglia and IL-6 production via toll-like receptor 2 (TLR2) and the JNK/c-Jun pathway, leading to AP-1 activation.

Area of Science:

  • Immunology
  • Microbiology
  • Neuroscience

Background:

  • Peptidoglycan (PGN), a bacterial cell wall component, is known to activate NF-κB and microglia.
  • The precise mechanisms by which PGN influences AP-1 activation and cytokine expression, specifically IL-6, in microglia remain incompletely understood.

Purpose of the Study:

  • To investigate the signaling pathways involved in PGN-induced IL-6 production in microglia.
  • To elucidate the role of toll-like receptors (TLRs), JNK/c-Jun, and AP-1 in this process.

Main Methods:

  • Microglia were treated with PGN, and IL-6 mRNA and protein levels were measured.
  • TLR2 and TLR4 expression were assessed.
  • siRNA and neutralizing antibodies targeting TLR2 were used.
  • Inhibitors of JNK/c-Jun (SP600125) and AP-1 (Tanshinone IIA, curcumin) were administered.
  • Western blotting, electrophoretic mobility shift assays (EMSA), and reporter gene assays were performed.

Main Results:

  • PGN dose- and time-dependently increased IL-6 mRNA and protein levels.
  • PGN upregulated TLR2 expression but not TLR4.
  • TLR2 inhibition blocked PGN-induced IL-6 production.
  • JNK and c-Jun phosphorylation, as well as JNK kinase activity, were increased by PGN.
  • AP-1 inhibitors reduced PGN-induced IL-6 expression.
  • PGN promoted c-Fos and phospho-c-Jun nuclear translocation and AP-1 DNA binding.
  • PGN enhanced IL-6 promoter activity, which was antagonized by JNK inhibition or AP-1 inhibitors.

Conclusions:

  • PGN-induced IL-6 expression in microglia is mediated by AP-1 activation.
  • This activation occurs through the TLR2 and JNK/c-Jun signaling pathways.

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