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

研究成果: Article査読

4 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)574-578
ページ数5
ジャーナルBiochemical and Biophysical Research Communications
354
2
DOI
出版ステータスPublished - 2007 3 9
外部発表はい

ASJC Scopus subject areas

  • 生物理学
  • 生化学
  • 分子生物学
  • 細胞生物学

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