TLR ligands induce synergistic interferon-β and interferon-λ1 gene expression in human monocyte-derived dendritic cells.
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.
Department of Vaccination and Immune Protection, National Institute for Heath and Welfare, PO Box 30, FI-00271 Helsinki, Finland. sanna.makela@thl.fi
Sanna M
SM
Mäkelä
Pamela
P
Osterlund
Ilkka
I
Julkunen
D045142:Cross-Priming / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics* / Q000378:metabolism; D007372:Interferons; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009500:Neutralization Tests; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011070:Poly I-C / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000095022:Interferon Lambda
D007093:Imidazoles; D050835:Interferon Regulatory Factors; D016899:Interferon-beta; D007372:Interferons; D007378:Interleukins; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011070:Poly I-C; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C402365:resiquimod