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, G. Szabó

Research output: Contribution to journalArticle

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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 2005

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Toll-Like Receptor 2
Propionibacterium acnes
Cytokines
Liver
Wounds and Injuries
Lipopolysaccharides
Interferons
Peritoneal Macrophages
Ligands
Interleukin-6
Interleukins
Hepatocytes
Necrosis
Tumor Necrosis Factor-alpha
Interleukin-18
Acute Liver Failure
Peptidoglycan
Gram-Positive Bacteria
Interleukin-12
Cricetulus

Keywords

  • IFN-γ
  • LPS
  • TLR4
  • TLR9

ASJC Scopus subject areas

  • Cell Biology

Cite this

Toll-like receptor 2 mediates inflammatory cytokine induction but not sensitization for liver injury by Propionibacterium acnes. / Romics, Laszlo; Dolganiuc, Angela; Velayudham, Arumugam; Kodys, Karen; Mandrekar, Pranoti; Golenbock, Douglas; Kurt-Jones, Evelyn; Szabó, G.

In: Journal of Leukocyte Biology, Vol. 78, No. 6, 12.2005, p. 1255-1264.

Research output: Contribution to journalArticle

Romics, L, Dolganiuc, A, Velayudham, A, Kodys, K, Mandrekar, P, Golenbock, D, Kurt-Jones, E & Szabó, G 2005, 'Toll-like receptor 2 mediates inflammatory cytokine induction but not sensitization for liver injury by Propionibacterium acnes', Journal of Leukocyte Biology, vol. 78, no. 6, pp. 1255-1264. https://doi.org/10.1189/jlb.0804448
Romics, Laszlo ; Dolganiuc, Angela ; Velayudham, Arumugam ; Kodys, Karen ; Mandrekar, Pranoti ; Golenbock, Douglas ; Kurt-Jones, Evelyn ; Szabó, G. / Toll-like receptor 2 mediates inflammatory cytokine induction but not sensitization for liver injury by Propionibacterium acnes. In: Journal of Leukocyte Biology. 2005 ; Vol. 78, No. 6. pp. 1255-1264.
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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.",
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AU - Kurt-Jones, Evelyn

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