title: High mobility group B1 protein suppresses the human plasmacytoid dendritic cell response to TLR9 agonists.
abstract: Plasmacytoid dendritic cells (PDC) are innate immune effector cells that are recruited to sites of chronic inflammation, where they modify the quality and nature of the adaptive immune response. PDCs modulate adaptive immunity in response to signals delivered within the local inflammatory milieu by pathogen- or damage-associated molecular pattern, molecules, and activated immune cells (including NK, T, and myeloid dendritic cells). High mobility group B1 (HMGB1) is a recently identified damage-associated molecular pattern that is released during necrotic cell death and also secreted from activated macrophages, NK cells, and mature myeloid dendritic cells. We have investigated the effect of HMGB1 on the function of PDCs. In this study, we demonstrate that HMGB1 suppresses PDC cytokine secretion and maturation in response to TLR9 agonists including the hypomethylated oligodeoxynucleotide CpG- and DNA-containing viruses. HMGB1-inhibited secretion of several proinflammatory cytokines including IFN-alpha, IL-6, TNF-alpha, inducible protein-10, and IL-12. In addition, HMGB1 prevented the CpG induced up-regulation of costimulatory molecules on the surface of PDC and potently suppressed their ability to drive generation of IFN-gamma-secreting T cells. Our observations suggest that HMGB1 may play a critical role in regulating the immune response during chronic inflammation and tissue damage through modulation of PDC function.
authors.affiliation: Division of Surgical Oncology, Department of Surgery and Molecular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15232, USA.
authors.forename: Petar J
authors.initials: PJ
authors.lastname: Popovic
authors.forename: Richard
authors.initials: R
authors.lastname: DeMarco
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.forename: Steven E
authors.initials: SE
authors.lastname: Winikoff
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Krieg
authors.forename: Z Sheng
authors.initials: ZS
authors.lastname: Guo
authors.forename: Charles K
authors.initials: CK
authors.lastname: Brown
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Zeh
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004267:DNA Viruses; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D024243:HMGB1 Protein / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology*
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D009838:Oligodeoxyribonucleotides; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9