Abstract
High mobility group box 1 (HMGB1) is an abundant and conserved nuclear protein that is released by necrotic cells and acts in the extracellular environment as a primary proinflammatory signal. In this study we show that human dendritic cells, which are specialized in Ag presentation to T cells, actively release their own HMGB1 into the extracellular milieu upon activation. This secreted HMGB1 is necessary for the up-regulation of CD80, CD83, and CD86 surface markers of human dendritic cells and for IL-12 production. The HMGB1 secreted by dendritic cells is also required for the clonal expansion, survival, and functional polarization of naive T cells. Using neutralizing Abs and receptor for advanced glycation end product-deficient (RAGE(-/-)) cells, we demonstrate that RAGE is required for the effect of HMGB1 on dendritic cells. HMGB1/RAGE interaction results in downstream activation of MAPKs and NF-kappaB. The use of an ancient signal of necrosis, HMGB1, by dendritic cells to sustain their own maturation and for activation of T lymphocytes represents a profitable evolutionary mechanism.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / physiology
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / physiology
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Cell Differentiation / physiology
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Cell Proliferation
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Cell Survival / physiology
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Cells, Cultured
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Clone Cells
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Coculture Techniques
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Cytosol / metabolism
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Dendritic Cells / cytology
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism*
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Extracellular Signal-Regulated MAP Kinases / physiology
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Extracellular Space / metabolism
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Growth Inhibitors / pharmacology
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HMGB1 Protein / metabolism*
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HMGB1 Protein / physiology
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Humans
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Immune Sera / pharmacology
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Interleukin-12 / biosynthesis
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Lymphocyte Activation / physiology*
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NF-kappa B / physiology
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Receptor for Advanced Glycation End Products
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Receptors, Immunologic / metabolism*
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Resting Phase, Cell Cycle / physiology
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / physiology*
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Th1 Cells / cytology
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Th1 Cells / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
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p38 Mitogen-Activated Protein Kinases / physiology
Substances
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Growth Inhibitors
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HMGB1 Protein
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Immune Sera
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NF-kappa B
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Receptor for Advanced Glycation End Products
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Receptors, Immunologic
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Interleukin-12
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases