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Published online before print October 4, 2005

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(Journal of Leukocyte Biology. 2005;78:1255-1264.)
© 2005 by Society for Leukocyte Biology

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

Laszlo Romics, Jr^*, Angela Dolganiuc^*, Arumugam Velayudham^*, Karen Kodys^*, Pranoti Mandrekar^*, Douglas Golenbock, Evelyn Kurt-Jones and Gyongyi Szabo^*,1

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

¹ Correspondence: Department of Medicine, University of Massachusetts Medical School, LRB 215, 364 Plantation Street, Worcester, MA 01605-2324. E-mail: gyongyi.szabo{at}umassmed.edu

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 (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-1ß, 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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