Published online before print October 4, 2005

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0804448

Received for publication August 9, 2004.
Revised April 8, 2005.
Accepted for publication July 27, 2005.

Article

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

Laszlo Romics Jr. ^*, Angela Dolganiuc ^*, Arumugam Velayudham ^*, Karen Kodys ^*, Pranoti Mandrekar ^*, Douglas Golenbock , Evelyn Kurt-Jones , and Gyongyi Szabo ^*@

Liver Center, Divisions of *Gastroenterology and Infectious Diseases, Department of Medicine, University of Massachusetts Medical School, Worcester

^@ To whom correspondence should be addressed. E-mail: gyongyi.szabo{at}umassmed.edu.

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 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 (MyD88)-dependent, and it was augmented by coexpression of CD14 in mouse peritoneal macrophages. In vitro, P. acnes behaved as a TLR2 ligand and induced TLR4 hetero- and TLR2 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 (TNF-), interleukin (IL)-6, interferon- (IFN-), and IL-12 (p40/p70), and increased RNA expression of proinflammatory cytokines (IL-12p40, IL-1, IL-6, IL-1, IL-18, IFN-) 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-, IFN-, IL-6, and liver proinflammatory cytokine mRNA expression. IFN-, 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.

Key Words: TLR4 • TLR9 • LPS • IFN-

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