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* Division of Surgical Oncology and
Translational Research, Department of Surgery and Molecular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15232;
Coley Pharmaceutical Group, Wellesley, MA 02481; and
Institute for Medical Research, North Shore-Long Island Jewish Research Institute, Manhasset, NY 11030
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-
, IL-6, TNF-, 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-
-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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by an American Society of Clinical Oncology Career Development Award (to H.J.Z.).
2 Address correspondence and reprint requests to Dr. Herbert J. Zeh III, Division of Surgical Oncology, University of Pittsburgh Cancer Institute, University of Pittsburgh Medical Center Cancer Pavilion, Suite 440, 5150 Center Avenue, Pittsburgh, PA 15232. E-mail address: zehh{at}upmc.edu
3 Abbreviations used in this paper: PDC, plasmacytoid dendritic cell; PAMP, pathogen-associated molecular pattern; DAMP, damage-associated molecular pattern; ODN, oligodeoxynucleotide; HMGB1, high mobility group B1; MDC, myeloid dendritic cell; IP-10, inducible protein-10; RAGE, the receptor for advanced glycation end products; RT, room temperature; MOI, multiplicity of infection; WRvv, Western Reserve vaccinia virus.
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