title: A variety of microbial components induce tolerance to lipopolysaccharide by differentially affecting MyD88-dependent and -independent pathways.
abstract: Exposure of macrophages to lipopolysaccharide (LPS) induces a hypo-responsive state to a second challenge with LPS that is termed LPS tolerance. LPS tolerance is also induced by pre-exposure to lipopeptides and lipoteichoic acid, which trigger Toll-like receptor (TLR) 2-mediated signaling. LPS signaling involves at least two pathways: a MyD88-dependent cascade that is essential for production of inflammatory cytokines and a MyD88-independent cascade that mediates the expression of IFN-inducible genes. We analyzed the induction of LPS tolerance by several microbial components in mouse peritoneal macrophages. Pre-exposure to LPS led to impaired activation of both the pathways. In contrast, mycoplasmal lipopeptides did not affect the MyD88-independent pathway, but impaired the MyD88-dependent signaling by inhibiting LPS-mediated activation of IL-1 receptor-associated kinase (IRAK) 1. The induction of LPS tolerance by recently identified TLR ligands was analyzed. Pretreatment with double-stranded RNA, which triggers the activation of TLR3, led to defective activation of the MyD88-independent, but not the MyD88-dependent, pathway. Imidazoquinoline compounds, which are recognized by TLR7, had no effect on the MyD88-independent pathway, but inhibited LPS-induced activation of MyD88-dependent signaling through down-regulation of IRAK1 expression. Thus, each microbial component induced LPS tolerance in macrophages.
authors.affiliation: Department of Host Defense, Research Institute for Microbial Diseases, Osaka University and Solution-oriented Research for Science and Technology, Japan Science and Technology Corporation, Suita, Osaka 565-0871, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Sato
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujita
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Tomizawa
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology* / Q000494:pharmacology; D002478:Cells, Cultured; D007093:Imidazoles / Q000494:pharmacology; D007108:Immune Tolerance; D053592:Interleukin-1 Receptor-Associated Kinases; D055666:Lipopeptides; D008070:Lipopolysaccharides / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016858:Mycoplasma fermentans / Q000737:chemistry / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88; D009842:Oligopeptides / Q000276:immunology* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D017472:Receptors, Interleukin-1 / Q000502:physiology; D012475:Salmonella / Q000737:chemistry / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D001426:Bacterial Proteins; D007093:Imidazoles; D055666:Lipopeptides; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; C106335:macrophage stimulatory lipopeptide 2; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; C402365:resiquimod