Abstract
Toll-like receptors (TLRs) are pattern-recognition receptors of the innate immune system that recognize various pathogen-associated molecules. TLR ligands are potent activators of immune cells and certain TLR ligands have a synergistic ability to induce the production of pro-inflammatory cytokines. In the present study we have analyzed the potential synergy between TLR3, TLR4 and TLR7/8 ligands in type I and type III interferon (IFN) gene expression in human monocyte-derived dendritic cells (moDCs). We show that stimulation of moDCs with TLR7/8 ligand R848 together with TLR3 or TLR4 ligands, polyI:C or LPS, respectively, leads to a synergistic expression of IFN-β and IFN-λ1 mRNAs. Neutralization of type I IFNs as well as IFN priming prior to stimulation suggest that IFN-dependent positive feedback loop is at least partly responsible for the mechanism of synergy. Enhanced expression of TLR3 and especially TLR7, which are both under the regulation of type I IFNs, correlated to synergistic TLR ligand-dependent induction of IFN-β and IFN-λ1 genes. NF-κB, PI3 kinase and MAP kinase pathways were involved in TLR ligand-induced IFN gene expression as evidenced by pharmacological signaling inhibitors. The data indicates that IFNs contribute to TLR-dependent gene activation in human DCs stimulated with multiple TLR ligands.
Copyright © 2010 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cross-Priming / drug effects
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Dendritic Cells / drug effects
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Dendritic Cells / enzymology
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Dendritic Cells / immunology*
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Gene Expression Regulation / drug effects
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Humans
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Imidazoles / pharmacology
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Interferon Regulatory Factors / genetics
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Interferon Regulatory Factors / metabolism
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Interferon-beta / genetics*
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Interferon-beta / metabolism
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Interferons
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Interleukins / genetics*
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Interleukins / metabolism
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Ligands
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Lipopolysaccharides / pharmacology
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Monocytes / cytology*
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Neutralization Tests
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Poly I-C / pharmacology
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Protein Binding / drug effects
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Protein Biosynthesis / drug effects
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Protein Kinase Inhibitors / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Response Elements / genetics
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Toll-Like Receptors / genetics
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Toll-Like Receptors / metabolism*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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interferon-lambda, human
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Imidazoles
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Interferon Regulatory Factors
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Interleukins
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Ligands
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Lipopolysaccharides
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NF-kappa B
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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RNA, Messenger
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Toll-Like Receptors
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Interferon-beta
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Interferons
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p38 Mitogen-Activated Protein Kinases
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Poly I-C
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resiquimod