Azuma Masahiro, Matsuo Aya, Fujimoto Yukari, Fukase Koichi, Hazeki Kaoru, Hazeki Osamu, Matsumoto Misako, Seya Tsukasa
Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Sapporo 060-8638, Japan.
Biochem Biophys Res Commun. 2007 Mar 9;354(2):574-8. doi: 10.1016/j.bbrc.2007.01.019. Epub 2007 Jan 10.
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.
脂多糖（LPS）是革兰氏阴性菌外膜的主要成分，由多糖和一种名为脂质A的脂质结构组成。脂质A是一种典型的微生物模式分子，作为Toll样受体4（TLR4）的配体。TLR4识别脂质A的存在，招募接头分子，并通过激活转录因子NF-κB或IRF-3诱导细胞因子和I型干扰素（IFN）。在此，我们表明，化学合成的TLR4激动剂脂质A类似物而非拮抗剂脂质A可在表达TLR4的HEK293细胞中激活IFN-β启动子。IFN-β启动子激活的幅度与NF-κB的幅度平行。在该系统中，有效诱导IFN-β需要LPS结合蛋白（LBP），而杀菌/通透性增加蛋白（BPI）可拮抗这种LBP活性。因此，我们首次表明，通过向脂质A敏感细胞外源性给予BPI，BPI可阻断TLR4反应。尽管细胞外BPI调节由TLR接头分子MyD88和TICAM-1（TRIF）选择的细胞内信号通路的功能机制尚不清楚，但我们推测LPS的脂质A部分参与LBP放大的IFN-β诱导，并且BPI与LPS的结合通过TLR4以非内在模式导致LPS或激动剂脂质A对NF-κB和IFN-β激活的抑制。BPI可能通过作为LPS-TLR4信号通路中MyD88和TICAM-1途径的调节剂，对内毒素休克具有治疗潜力。
