title: The attenuated inflammation of MPL is due to the lack of CD14-dependent tight dimerization of the TLR4/MD2 complex at the plasma membrane.
abstract: TLR4/MD-2 senses lipid A, activating the MyD88-signaling pathway on the plasma membrane and the TRIF-signaling pathway after CD14-mediated TLR4/MD-2 internalization into endosomes. Monophosphoryl lipid A (MPL), a detoxified derivative of lipid A, is weaker than lipid A in activating the MyD88-dependent pathway. Little is known, however, about mechanisms underlying the attenuated activation of MyD88-dependent pathways. We here show that MPL was impaired in induction of CD14-dependent TLR4/MD-2 dimerization compared with lipid A. Impaired TLR4/MD-2 dimerization decreased CD14-mediated TNFα production. In contrast, MPL was comparable to lipid A in CD14-independent MyD88-dependent TNFα production and TRIF-dependent responses including cell surface CD86 up-regulation and IFNβ induction. Although CD86 up-regulation is dependent on TRIF signaling, it was induced by TLR4/MD-2 at the plasma membrane. These results revealed that the attenuated MPL responses were due to CD14-initiated responses at the plasma membrane, but not just to responses initiated by MyD88, that is, MPL was specifically unable to induce CD14-dependent TLR4/MD-2 dimerization that selectively enhances MyD88-mediated responses at the plasma membrane.
authors.affiliation: Division of Innate Immunity, Institute of Medical Science, the University of Tokyo, Tokyo 108-8639, Japan Japan Society for the Promotion of Science, Tokyo 102-8472, Japan natsuko@ims.u-tokyo.ac.jp.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Tanimura
authors.affiliation: Division of Innate Immunity, Institute of Medical Science, the University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Shin-Ichiroh
authors.initials: S
authors.lastname: Saitoh
authors.affiliation: The Graduate School of Pharmaceutical Science, University of Tokyo, Tokyo 113-8654, Japan.
authors.forename: Umeharu
authors.initials: U
authors.lastname: Ohto
authors.affiliation: Division of Innate Immunity, Institute of Medical Science, the University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Akashi-Takamura
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University, Osaka 560-0043, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Fujimoto
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University, Osaka 560-0043, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukase
authors.affiliation: The Graduate School of Pharmaceutical Science, University of Tokyo, Tokyo 113-8654, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Division of Innate Immunity, Institute of Medical Science, the University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000276:immunology; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D019281:Dimerization; D007249:Inflammation / Q000276:immunology; D008050:Lipid A / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D033942:Adaptor Proteins, Vesicular Transport; D019138:Antibodies, Blocking; D051940:B7-2 Antigen; D002352:Carrier Proteins; D008050:Lipid A; D018950:Lipopolysaccharide Receptors; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000099231:Lipopolysaccharide-Binding Protein; C470409:TICAM1 protein, human; C048436:monophosphoryl lipid A
keywords: CD14; LBP; MPL; TLR4/MD-2