Toll-like receptor 2 mediates inflammatory cytokine induction but not sensitization for liver injury by Propionibacterium acnes

Laszlo Romics, Angela Dolganiuc, Arumugam Velayudham, Karen Kodys, Pranoti Mandrekar, Douglas Golenbock, Evelyn Kurt-Jones, Gyongyi Szabo

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27 Citations (Scopus)

Abstract

Recognition of Gram-positive bacteria by Toll-like receptor 2 (TLR2) induces activation of proinflammatory pathways. In mice, sensitization with the Gram-positive Propionibacterium acnes followed by a challenge with the TLR4 ligand, lipopolysaccharide (LPS), results in fulminant hepatic failure. Here, we investigated the role of TLR2 in liver sensitization to LPS-induced injury. Stimulation of Chinese hamster ovary cells and peritoneal macrophages with heat-killed P. acnes required expression of TLR2 but not of TLR4, suggesting that P. acnes was a TLR2 ligand. Cell activation by P. acnes was myeloid differentiation primary-response protein 88 (MyB88)-dependent, and it was augmented by coexpression of CD 14 in mouse peritoneal macrophages. In vitro, P. acnes behaved as a TLR2 ligand and induced TLR4 hetero- and TLK2 homotolerance in peritoneal macrophages. In vivo priming of wild-type mice with P. acnes, but not with the selective TLR2 ligands peptidoglycan and lipotheicoic acid, resulted in hepatocyte necrosis, hyperelevated serum levels of tumor necrosis factor α (TNF-α), interleukin (IL)-6, interferon-γ (IFN-γ), and IL-12 (p40/p70), and increased RNA expression of proinflammatory cytokines (IL-12p40, IL-1a, IL-6, IL-1β, IL-18, IFN-γ) in the liver after a LPS challenge. Furthermore, P. acnes priming sensitized TLR2-deficient (TLR2-/-) but not MyD88-/- mice to LPS-induced injury, evidenced by hepatocyte necrosis, increased levels of serum TNF-α, IFN-γ, IL-6, and liver proinflammatory cytokine mRNA expression. IFN-γ, a cytokine sensitizing to endotoxin, was induced by P. acnes in splenocytes of TLR2-/- and TLR9-/- but not MyD88-/- mice. These results suggest that although P. acnes triggers TLR2-mediated cell activation, TLR2-independent but MyD88-dependent mechanisms mediate in vivo sensitization by P. acnes for LPS-induced liver injury.

Original languageEnglish
Pages (from-to)1255-1264
Number of pages10
JournalJournal of Leukocyte Biology
Volume78
Issue number6
DOIs
Publication statusPublished - Dec 1 2005

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Keywords

  • IFN-γ
  • LPS
  • TLR4
  • TLR9

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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