TY - JOUR
T1 - Inhibition of lipid A-mediated type I interferon induction by Bactericidal/permeability-increasing protein (BPI)
AU - Azuma, Masahiro
AU - Matsuo, Aya
AU - Fujimoto, Yukari
AU - Fukase, Koichi
AU - Hazeki, Kaoru
AU - Hazeki, Osamu
AU - Matsumoto, Misako
AU - Seya, Tsukasa
PY - 2007/3/9
Y1 - 2007/3/9
N2 - 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.
AB - 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.
KW - Chemically synthesized lipid A
KW - Interferon-beta
KW - TICAM-1
KW - Toll-like receptor
UR - http://www.scopus.com/inward/record.url?scp=33846491827&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33846491827&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2007.01.019
DO - 10.1016/j.bbrc.2007.01.019
M3 - Article
C2 - 17239348
AN - SCOPUS:33846491827
VL - 354
SP - 574
EP - 578
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 2
ER -