title: Enterovirus-71 virus-like particles induce the activation and maturation of human monocyte-derived dendritic cells through TLR4 signaling.
abstract: Enterovirus 71 (EV71) causes seasonal epidemics of hand-foot-and-mouth disease and has a high mortality rate among young children. We recently demonstrated potent induction of the humoral and cell-mediated immune response in monkeys immunized with EV71 virus-like particles (VLPs), with a morphology resembling that of infectious EV71 virions but not containing a viral genome, which could potentially be safe as a vaccine for EV71. To elucidate the mechanisms through which EV71 VLPs induce cell-mediated immunity, we studied the immunomodulatory effects of EV71 VLPs on human monocyte-derived dendritic cells (DCs), which bind to and incorporate EV71 VLPs. DC treatment with EV71 VLPs enhanced the expression of CD80, CD86, CD83, CD40, CD54, and HLA-DR on the cell surface; increased the production of interleukin (IL)-12 p40, IL-12 p70, and IL-10 by DCs; and suppressed the capacity of DCs for endocytosis. Treatment with EV71 VLPs also enhanced the ability of DCs to stimulate naïve T cells and induced secretion of interferon (IFN)-γ by T cells and Th1 cell responses. Neutralization with antibodies against Toll-like receptor (TLR) 4 suppressed the capacity of EV71 VLPs to induce the production of IL-12 p40, IL-12 p70, and IL-10 by DCs and inhibited EV71 VLPs binding to DCs. Our study findings clarified the important role for TLR4 signaling in DCs in response to EV71 VLPs and showed that EV71 VLPs induced inhibitor of kappaB alpha (IκBα) degradation and nuclear factor of kappaB (NF-κB) activation.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yu-Li
authors.initials: YL
authors.lastname: Lin
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Hu
authors.affiliation: Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan.
authors.forename: Cheng-Chao
authors.initials: CC
authors.lastname: Liang
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Shih-Yeh
authors.initials: SY
authors.lastname: Lin
authors.affiliation: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Liang
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Yuan
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Bor-Luen
authors.initials: BL
authors.lastname: Chiang
mesh_terms: D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism*; D004705:Endocytosis; D029821:Enterovirus A, Human / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D056747:Immunomodulation; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D059748:Proteolysis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014771:Virion / Q000378:metabolism*
chemical_list: D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000072000:NF-KappaB Inhibitor alpha