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
N1 - Funding Information:
This work was supported in part by CREST, JST (Japan Science and Technology Corporation), by the HCV project in NIH of Japan, and by the Naito Memorial Foundation, Uehara memorial Foundation, Mitsubishi Foundation, Northtic Foundation, and Takeda Foundation. We are grateful to Drs. A. Ishii, T. Ebihara, and A. Funami (Seya labo) and Y. Fukase and Y. Adachi (Fukase labo) for their critical discussions.
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
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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 -