Funiculosin variants and phosphorylated derivatives promote innate immune responses via the Toll-like receptor 4/myeloid differentiation factor-2 complex

被引:5
作者
Okamoto, Naoki [1 ,2 ]
Mizote, Keisuke [3 ]
Honda, Hiroe [1 ,4 ]
Saeki, Akinori [3 ]
Watanabe, Yasuharu [1 ]
Yamaguchi-Miyamoto, Tomonni [4 ]
Fukui, Ryutaro [5 ]
Tanimura, Natsuko [5 ]
Motoi, Yuji [5 ]
Akashi-Takamura, Sachiko [6 ]
Kato, Tatsuhisa [2 ]
Fujishita, Shigeto [2 ]
Kimura, Takahito [2 ]
Ohto, Umeharu [7 ]
Shimizu, Toshiyuki [7 ]
Hirokawa, Takatsugu [8 ,9 ]
Miyake, Kensuke [5 ,10 ]
Fukase, Koichi [3 ]
Fujimoto, Yukari [11 ]
Nagai, Yoshinori [1 ,12 ]
Takatsu, Kiyoshi [1 ,4 ]
机构
[1] Univ Toyama, Grad Sch Med & Pharmaceut Sci Res, Dept Immunobiol & Pharmacol Genet, 2630 Sugitani, Toyama 9300194, Japan
[2] Teika Pharmaceut Co Ltd, 1-3-27 Arakawa, Toyama 9300982, Japan
[3] Osaka Univ, Sch Sci, Dept Chem, Lab Nat Prod Chem, 1-1 Machikaneyama, Toyonaka, Osaka 5600043, Japan
[4] Toyama Prefectural Inst Pharmaceut Res, 17-1 Nakataikouyama, Imizu, Toyama 9390363, Japan
[5] Univ Tokyo, Inst Med Sci, Dept Microbiol & Immunol, Div Innate Immun,Minato Ku, 4-6-1 Shirokanedai, Tokyo 1088639, Japan
[6] Aichi Med Univ, Sch Med, Dept Microbiol & Immunol, 1-1 Yazakokarimata, Nagakute, Aichi 4801195, Japan
[7] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan
[8] AIST, Mol Profiling Res Ctr Drug Discovery, Koto Ku, 2-3-26 Aomi, Tokyo 1350064, Japan
[9] Univ Tsukuba, Div Biomed Sci, Fac Med, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan
[10] Univ Tokyo, Inst Med Sci, Ctr Expt Med & Syst Biol, Lab Innate Immun,Minato Ku, 4-6-1 Shirokanedai, Tokyo 1088639, Japan
[11] Keio Univ, Fac Sci & Technol, Dept Chem, Kohoku Ku, 3-14-1 Hiyoshi, Yokohama, Kanagawa 2238522, Japan
[12] Japan Sci & Technol Agcy JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 3320012, Japan
基金
日本学术振兴会;
关键词
LIPOPOLYSACCHARIDE (LPS)-BINDING PROTEIN; CELL-SURFACE EXPRESSION; MONOPHOSPHORYL-LIPID-A; DENDRITIC CELLS; CRYSTAL-STRUCTURES; ACCURATE DOCKING; STRUCTURAL BASIS; GENE-EXPRESSION; CUTTING EDGE; B-CELLS;
D O I
10.1074/jbc.M117.791780
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD-2) complex is essential for LPS recognition and induces innate immune responses against Gram-negative bacteria. As activation of TLR4/MD-2 is also critical for the induction of adaptive immune responses, TLR4/MD-2 agonists have been developed as vaccine adjuvants, but their efficacy has not yet been ascertained. Here, we demonstrate that a funiculosin (FNC) variant, FNC-RED, and FNC-RED and FNC derivatives are agonists for both murine and human TLR4/MD-2. FNC-RED induced nuclear factor-kappa B (NF-kappa B) activation via murine TLR4/MD-2, whereas FNC had no TLR4/MD-2 stimulatory activity. Biacore analysis revealed that FNC-RED binds to murine TLR4/MD-2 but not murine radioprotective 105 (RP105)/myeloid differentiation factor-1 (MD-1), another LPS sensor. FNC-RED induced CD14-independent expressions of pro-inflammatory cytokines and co-stimulatory molecules in murine macrophages and dendritic cells. In contrast, FNC-RED stimulation was reduced in CD14-dependent LPS responses, including dimerization and internalization of TLR4/MD-2 and IFN-beta expression. FNC-RED-induced IL-12p40 production from murine dendritic cells was dependent on NF-kappa B but not MAPK pathway. In addition, fetal bovine serum augmented lipid A-induced NF-kappa B activation but blocked FNC-RED-mediated responses. Two synthetic phosphate group-containing FNC-RED and FNC derivatives, FNC-RED-P01 and FNC-P01, respectively, activated human TLR4/MD-2, unlike FNC-RED. Finally, computational analysis revealed that this species-specific activation by FNC-RED and FNC-RED-P01 resulted from differences in electrostatic surface potentials between murine and human TLR4/MD-2. We conclude that FNC-RED and its synthetic derivative represent a novel category of murine and human TLR4/MD-2 agonist.
引用
收藏
页码:15378 / 15394
页数:17
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