title: Toll-like receptor 2 mediates inflammatory cytokine induction but not sensitization for liver injury by Propioni- bacterium acnes.
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 (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-1alpha, IL-6, IL-1beta, IL-18, IFN-gamma) 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-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-/- 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.
authors.affiliation: Liver Center, Department of Medicine, University of Massachusetts Medical School, LRB 215, 364 Plantation Street, Worcester, MA 01605-2324, USA.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Romics
authors.forename: Angela
authors.initials: A
authors.lastname: Dolganiuc
authors.forename: Arumugam
authors.initials: A
authors.lastname: Velayudham
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.forename: Pranoti
authors.initials: P
authors.lastname: Mandrekar
authors.forename: Douglas
authors.initials: D
authors.lastname: Golenbock
authors.forename: Evelyn
authors.initials: E
authors.lastname: Kurt-Jones
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology; D016466:CHO Cells; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D006224:Cricetinae; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D016908:Gram-Positive Bacterial Infections / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D006505:Hepatitis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology*; D018836:Inflammation Mediators / Q000097:blood / Q000276:immunology*; D008024:Ligands; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D017114:Liver Failure, Acute / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D011424:Propionibacterium / Q000276:immunology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D016207:Cytokines; D018836:Inflammation Mediators; D008024:Ligands; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D011971:Receptors, Immunologic; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2