title: TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant.
abstract: High mobility group box protein 1 (HMGB1) acts as an endogenous danger molecule that is released from necrotic cells and activated macrophages. We have previously shown that peptide Hp91, whose sequence corresponds to an area within the B-Box domain of HMGB1, activates dendritic cells (DCs) and acts as an adjuvant in vivo. Here we investigated the underlying mechanisms of Hp91-mediated DC activation. Hp91-induced secretion of IL-6 was dependent on clathrin- and dynamin-driven endocytosis of Hp91 and mediated through a MyD88- and TLR4-dependent pathway involving p38 MAPK and NFκB. Endosomal TLR4 has been shown to activate the MyD88-independent interferon pathway. Hp91-induced activation of pIRF3 and IL-6 secretion was reduced in IFNαβR knockout DCs, suggesting an amplification loop via the IFNαβR. These findings elucidate the mechanisms by which Hp91 acts as immunostimulatory peptide and may serve as a guide for the future development of synthetic Th1-type peptide adjuvants for vaccines.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Saenz
authors.forename: Diahnn
authors.initials: D
authors.lastname: Futalan
authors.forename: Lien
authors.initials: L
authors.lastname: Leutenez
authors.forename: Fien
authors.initials: F
authors.lastname: Eekhout
authors.forename: Jessie F
authors.initials: JF
authors.lastname: Fecteau
authors.forename: Simeon
authors.initials: S
authors.lastname: Sundelius
authors.forename: Stig
authors.initials: S
authors.lastname: Sundqvist
authors.forename: Marie
authors.initials: M
authors.lastname: Larsson
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hayashi
authors.forename: Boris
authors.initials: B
authors.lastname: Minev
authors.forename: Dennis
authors.initials: D
authors.lastname: Carson
authors.forename: Sadik
authors.initials: S
authors.lastname: Esener
authors.affiliation: Rebecca and John Moores Cancer Center, University of California San Diego (UCSD), 3855 Health Sciences Dr,, La Jolla, CA 92093-0815, USA. bmessmer@ucsd.edu.
authors.forename: Bradley
authors.initials: B
authors.lastname: Messmer
authors.forename: Davorka
authors.initials: D
authors.lastname: Messmer
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D005260:Female; D024243:HMGB1 Protein / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*
chemical_list: D000276:Adjuvants, Immunologic; D024243:HMGB1 Protein; D010446:Peptide Fragments; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4