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

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 alpha (TNF- alpha ), interleukin (IL)-6, interferon- gamma (IFN- gamma ), and IL-12 (p40/p70), and increased RNA expression of proinflammatory cytokines (IL-12p40, IL-1 alpha , IL-6, IL-1 beta , IL-18, IFN- gamma ) in the liver after a LPS challenge. Furthermore, P. acnes priming sensitized TLR2-deficient (TLR2 super(-/-)) but not MyD88 super(-/-) mice to LPS-induced injury, evidenced by hepatocyte necrosis, increased levels of serum TNF- alpha , IFN- gamma , IL-6, and liver proinflammatory cytokine mRNA expression. IFN- gamma , a cytokine sensitizing to endotoxin, was induced by P. acnes in splenocytes of TLR2 super(-/-) and TLR9 super(-/-) but not MyD88 super(-/-) 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.