Inhibition of lipid A-mediated type I interferon induction by Bactericidal/permeability-increasing protein (BPI)

Masahiro Azuma, Aya Matsuo, Yukari Fujimoto, Koichi Fukase, Kaoru Hazeki, Osamu Hazeki, Misako Matsumoto, Tsukasa Seya

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Lipopolysaccharide (LPS), a major constituent of the outer membrane of gram-negative bacteria, consists of polysaccharides and a lipid structure named lipid A. Lipid A is a typical microbial pattern molecule that serves as a ligand for Toll-like receptor 4 (TLR4). TLR4 signals the presence of lipid A to recruit adaptor molecules and induces cytokines and type I interferon (IFN) by activating transcription factor, NF-κB or IRF-3. Here we showed that chemically synthesized TLR4-agonistic lipid A analogues but not antagonistic lipid A activate IFN-β promoter in TLR4-expressing HEK293 cells. The amplitude of IFN-β promoter activation was in parallel with that of NF-κB. LPS-binding protein (LBP) was required for efficient IFN-β induction in this system, and this LBP activity was antagonized by bactericidal/permeability-increasing protein (BPI). Thus, we first show that BPI blocks the TLR4 responses by exogenous administration of BPI to lipid A-sensitive cells. Although the functional mechanism whereby extra-cellular BPI modulates the intra-cellular signal pathways selected by the TLR adaptors, MyD88 and TICAM-1 (TRIF), remains unknown, we infer that the lipid A portion of LPS participates in LBP-amplified IFN-β induction and that BPI binding to LPS leads to inhibition of the activation of NF-κB and IFN-β by LPS or agonistic lipid A via TLR4 in an extrinsic mode. BPI may serve as a therapeutic potential against endotoxin shock by acting as a regulator for the MyD88- and TICAM-1 pathways in the LPS-TLR4 signaling.

Original languageEnglish
Pages (from-to)574-578
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume354
Issue number2
DOIs
Publication statusPublished - 2007 Mar 9
Externally publishedYes

Keywords

  • Chemically synthesized lipid A
  • Interferon-beta
  • TICAM-1
  • Toll-like receptor

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Inhibition of lipid A-mediated type I interferon induction by Bactericidal/permeability-increasing protein (BPI)'. Together they form a unique fingerprint.

  • Cite this