Funiculosin variants and phosphorylated derivatives promote innate immune responses via the Toll-like receptor 4/myeloid differentiation factor-2 complex
| Autor: | Toshiyuki Shimizu, Akinori Saeki, Shigeto Fujishita, Takahito Kimura, Hiroe Honda, Tatsuhisa Kato, Kensuke Miyake, Tomomi Yamaguchi-Miyamoto, Natsuko Tanimura, Naoki Okamoto, Ryutaro Fukui, Yoshinori Nagai, Yuji Motoi, B. Umeharu Ohto, Yukari Fujimoto, Koichi Fukase, Kiyoshi Takatsu, Takatsugu Hirokawa, Keisuke Mizote, Yasuharu Watanabe, Sachiko Akashi-Takamura |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Pyridones Recombinant Fusion Proteins Immunology Lymphocyte Antigen 96 Bone Marrow Cells Biology Ligands Biochemistry Cell Line Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Immune system Animals Humans Phosphorylation Receptor Molecular Biology Cells Cultured Mice Knockout Toll-like receptor Binding Sites Innate immune system Macrophages Models Immunological Computational Biology Dendritic Cells Cell Biology Dendritic cell Molecular biology Immunity Innate Specific Pathogen-Free Organisms Mice Inbred C57BL Molecular Docking Simulation Toll-Like Receptor 4 030104 developmental biology Drug Design TLR4 Fetal bovine serum 030215 immunology |
| Zdroj: | Journal of Biological Chemistry. 292:15378-15394 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m117.791780 |
| Popis: | 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-κB (NF-κB) 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-β expression. FNC-RED-induced IL-12p40 production from murine dendritic cells was dependent on NF-κB but not MAPK pathway. In addition, fetal bovine serum augmented lipid A-induced NF-κB 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. |
| Databáze: | OpenAIRE |
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