The attenuated inflammation of MPL is due to the lack of CD14-dependent tight dimerization of the TLR4/MD2 complex at the plasma membrane

Natsuko Tanimura, Shin Ichiroh Saitoh, Umeharu Ohto, Sachiko Akashi-Takamura, Yukari Fujimoto, Koichi Fukase, Toshiyuki Shimizu, Kensuke Miyake

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 TNFa 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.

Original languageEnglish
Article numberdxt071
Pages (from-to)307-314
Number of pages8
JournalInternational immunology
Volume26
Issue number6
DOIs
Publication statusPublished - 2014 Jun
Externally publishedYes

Keywords

  • CD14
  • LBP
  • MPL
  • TLR4/MD-2

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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