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.
Keywords:
CD14; LBP; MPL; TLR4/MD-2.
© The Japanese Society for Immunology. 2013. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Publication types
-
Comparative Study
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acute-Phase Proteins / genetics
-
Acute-Phase Proteins / immunology
-
Adaptor Proteins, Vesicular Transport / metabolism
-
Animals
-
Antibodies, Blocking / pharmacology
-
B7-2 Antigen / genetics
-
B7-2 Antigen / metabolism
-
Carrier Proteins / genetics
-
Carrier Proteins / immunology
-
Cell Membrane / metabolism*
-
Cells, Cultured
-
Dendritic Cells / immunology*
-
Dimerization
-
Inflammation / immunology
-
Lipid A / administration & dosage*
-
Lipid A / analogs & derivatives*
-
Lipopolysaccharide Receptors / genetics
-
Lipopolysaccharide Receptors / metabolism
-
Lymphocyte Antigen 96 / genetics
-
Lymphocyte Antigen 96 / metabolism*
-
Membrane Glycoproteins / genetics
-
Membrane Glycoproteins / immunology
-
Mice
-
Mice, Inbred BALB C
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Myeloid Differentiation Factor 88 / metabolism
-
Signal Transduction / drug effects
-
Signal Transduction / genetics
-
Toll-Like Receptor 4 / genetics
-
Toll-Like Receptor 4 / metabolism*
-
Tumor Necrosis Factor-alpha / metabolism
-
Up-Regulation
Substances
-
Acute-Phase Proteins
-
Adaptor Proteins, Vesicular Transport
-
Antibodies, Blocking
-
B7-2 Antigen
-
Carrier Proteins
-
Lipid A
-
Lipopolysaccharide Receptors
-
Lymphocyte Antigen 96
-
Membrane Glycoproteins
-
Myeloid Differentiation Factor 88
-
TICAM1 protein, human
-
Toll-Like Receptor 4
-
Tumor Necrosis Factor-alpha
-
lipopolysaccharide-binding protein
-
monophosphoryl lipid A