title: Activation of dendritic cells by human papillomavirus-like particles through TLR4 and NF-kappaB-mediated signalling, moderated by TGF-beta.
abstract: Human papillomavirus-like particles (HPV-VLP) are a candidate vaccine for prevention of HPV infection, and also are a candidate for an immunogenic delivery system for incorporated antigen. VLP activate in vitro generated dendritic cells (DC) but not Langerhans cells (LC); however, the mechanism of this activation is unknown. We have shown that uptake and activation of DC by VLP involves proteoglycan receptors and can be inhibited by heparin. Heparin has been shown to activate DC by signalling through Toll-like receptor 4 (TLR4) and nuclear factor (NF)-kappaB. The pathway of DC activation by VLP was further investigated in the present study. Exposure to VLP induced costimulatory molecule expression, RelB translocation and IL-10 production by DC but not by LC. The lack of LC activation was reversible when TGF-beta was removed from the LC medium. VLP-induced induction of costimulatory molecule expression, RelB activation and cytokine secretion by DC was blocked by inhibition of NF-kappaB activation, heparin or TLR4 mAb. The data provide evidence that HPV-VLP signal DC through a pathway involving proteoglycan receptors, TLR4 and NF-kappaB, and shed light on the mechanism by which VLP stimulate immunity in the absence of adjuvants in vivo. LC may resist activation in normal epithelium abundant in TGF-beta, but not in situations in which TGF-beta concentrations are reduced.
authors.affiliation: Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Mengyong
authors.initials: M
authors.lastname: Yan
authors.forename: Judy
authors.initials: J
authors.lastname: Peng
authors.forename: Ibtissam A
authors.initials: IA
authors.lastname: Jabbar
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Liu
authors.forename: Luis
authors.initials: L
authors.lastname: Filgueira
authors.forename: Ian H
authors.initials: IH
authors.lastname: Frazer
authors.forename: Ranjeny
authors.initials: R
authors.lastname: Thomas
mesh_terms: D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D006801:Humans; D007109:Immunity; D016753:Interleukin-10 / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D027383:Papillomaviridae / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014771:Virion / Q000276:immunology
chemical_list: D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D051841:Transcription Factor RelB