Abstract
Two different CpG oligonucleotides (ODN) were used to study the regulation of type I IFN in human plasmacytoid dendritic cells (PDC): ODN 2216, a CpG-A ODN, known to induce high amounts of IFN-alpha in PDC, and ODN 2006, a CpG-B ODN, which is potent at stimulating B cells. CpG-A ODN showed higher and prolonged kinetics of type I IFN production compared with that of CpG-B ODN. In contrast, CpG-B ODN was more active than CpG-A ODN in stimulating IL-8 production and increasing costimulatory and Ag-presenting molecules, suggesting that CpG-A and CpG-B trigger distinct regulatory pathways in PDC. Indeed, CpG-A ODN, but not CpG-B ODN, activated the type I IFNR-mediated autocrine feedback loop. PDC were found to express high constitutive levels of IFN regulatory factor (IRF)7. IRF7 and STAT1, but not IRF3, were equally up-regulated by both CpG-A and CpG-B. CD40 ligand synergistically increased CpG-B-induced IFN-alpha independent of the IFNR but did not affect CpG-B-induced IFN-beta. In conclusion, our studies provide evidence for the existence of two distinct regulatory pathways of type I IFN synthesis in human PDC, one dependent on and one independent of the IFNR-mediated feedback loop. The alternate use of these pathways is based on the type of stimulus rather than the quantity of IFN-alphabeta available to trigger the IFNR. Constitutive expression of IRF7 and the ability to produce considerable amounts of IFN-alpha independent of the IFNR seem to represent characteristic features of PDC.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / antagonists & inhibitors
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Adjuvants, Immunologic / pharmacology
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Adolescent
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Adult
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Aged
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Antibodies, Monoclonal / metabolism
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Antigens, Surface / biosynthesis
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CD40 Ligand / pharmacology
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Cells, Cultured
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CpG Islands / immunology*
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Cytokines / biosynthesis
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DNA-Binding Proteins / biosynthesis
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism*
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Drug Combinations
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Feedback, Physiological / immunology
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Humans
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Interferon Regulatory Factor-3
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Interferon Regulatory Factor-7
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Interferon Type I / biosynthesis*
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Interferon Type I / metabolism
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Interferon-alpha / antagonists & inhibitors
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Interferon-alpha / biosynthesis
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Interferon-alpha / metabolism
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Interferon-beta / antagonists & inhibitors
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Interferon-beta / biosynthesis
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Kinetics
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Lectins, C-Type / immunology
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Lectins, C-Type / metabolism
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Ligands
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Membrane Glycoproteins
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Membrane Proteins
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Middle Aged
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Oligodeoxyribonucleotides / antagonists & inhibitors
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Oligodeoxyribonucleotides / pharmacology*
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Plasma Cells / immunology*
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Plasma Cells / metabolism*
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Receptor, Interferon alpha-beta
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Receptors, Immunologic
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Receptors, Interferon / physiology
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STAT1 Transcription Factor
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Signal Transduction / immunology*
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Trans-Activators / biosynthesis
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Transcription Factors / biosynthesis
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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Adjuvants, Immunologic
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Antibodies, Monoclonal
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Antigens, Surface
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CLEC4C protein, human
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CPG-oligonucleotide
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Cytokines
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DNA-Binding Proteins
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Drug Combinations
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IRF3 protein, human
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IRF7 protein, human
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Interferon Regulatory Factor-3
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Interferon Regulatory Factor-7
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Interferon Type I
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Interferon-alpha
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Lectins, C-Type
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Ligands
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Membrane Glycoproteins
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Membrane Proteins
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Oligodeoxyribonucleotides
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Receptors, Immunologic
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Receptors, Interferon
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STAT1 Transcription Factor
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STAT1 protein, human
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Trans-Activators
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Transcription Factors
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Tumor Necrosis Factor-alpha
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CD40 Ligand
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Receptor, Interferon alpha-beta
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Interferon-beta