Toll-Like Receptor Expression in Human Keratinocytes: Nuclear Factor κB Controlled Gene Activation by Staphylococcus aureus is Toll-Like Receptor 2 but Not Toll-Like Receptor 4 or Platelet Activating Factor Receptor Dependent

Martin Mempel*, Verena Voelcker, Gabriele Köllisch, Christian Plank, Roland Rad, Markus Gerhard, Christina Schnopp, Peter Fraunberger, Autar K. Walli, Johannes Ring, Dietrich Abeck, Markus Ollert

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

222 Citations (Scopus)

Abstract

Cultured primary human keratinocytes were screened for their expression of various members of the toll-like receptor (TLR) family. Keratinocytes were found to constitutively express TLR1, TLR2, TLR3, TLR5, and TLR9 but not TLR4, TLR6, TLR7, TLR8, or TLR10 as shown by polymerase chain reaction analysis. The expression of the crucial receptor for signaling of staphylococcal compounds TLR2 was also confirmed by immunohistochemistry, in contrast to TLR4, which showed a negative staining pattern. Next, we analyzed the activation of the proinflammatory nuclear transcription factor κB by Staphylococcus aureus strain 8325-4. Using nuclear extract gel shifts, RelA staining, and luciferase reporter transfection plasmids we found a clear induction of nuclear factor κB translocation by the bacteria. This translocation induced the transcription of nuclear factor κB controlled genes such as inducible nitric oxide synthetase, COX2, and interleukin-8. Transcription of these genes was followed by production of increased amounts of interleukin-8 protein and NO. Inhibition experiments using monoclonal antibodies and the specific platelet activating factor receptor inhibitor CV3988 showed that nuclear factor κB activation by S. aureus was TLR2 but not TLR4 or platelet activating factor receptor dependent. In line, the purified staphylococcal cell wall components lipoteichoic acid and peptidoglycan, known to signal through TLR2, also showed nuclear factor KB translocation in human keratinocytes, indicating a crucial role of the staphylococcal cell wall in the innate immune stimulation of human keratinocytes. These results help to explain the complex activation of human keratinocytes by S. aureus and its cell wall components in various inflammatory disorders of the skin.

Original languageEnglish
Pages (from-to)1389-1396
Number of pages8
JournalJournal of Investigative Dermatology
Volume121
Issue number6
DOIs
Publication statusPublished - Dec 2003
Externally publishedYes

Keywords

  • Bacterial cell wall
  • Infection
  • Proinflammatory activation

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