title: Inhibition of lipid A-mediated type I interferon induction by bactericidal/permeability-increasing protein (BPI).
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-kappaB or IRF-3. Here we showed that chemically synthesized TLR4-agonistic lipid A analogues but not antagonistic lipid A activate IFN-beta promoter in TLR4-expressing HEK293 cells. The amplitude of IFN-beta promoter activation was in parallel with that of NF-kappaB. LPS-binding protein (LBP) was required for efficient IFN-beta 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-beta induction and that BPI binding to LPS leads to inhibition of the activation of NF-kappaB and IFN-beta 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.
authors.affiliation: Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Sapporo 060-8638, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Azuma
authors.forename: Aya
authors.initials: A
authors.lastname: Matsuo
authors.forename: Yukari
authors.initials: Y
authors.lastname: Fujimoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukase
authors.forename: Kaoru
authors.initials: K
authors.lastname: Hazeki
authors.forename: Osamu
authors.initials: O
authors.lastname: Hazeki
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
mesh_terms: D000209:Acute-Phase Proteins / Q000037:antagonists & inhibitors; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000502:physiology*; D001798:Blood Proteins / Q000502:physiology*; D016466:CHO Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis* / Q000235:genetics; D008050:Lipid A / Q000037:antagonists & inhibitors*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D008565:Membrane Proteins / Q000502:physiology*; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D002352:Carrier Proteins; D007370:Interferon Type I; D008050:Lipid A; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D000099231:Lipopolysaccharide-Binding Protein; C021623:bactericidal permeability increasing protein