Article: article from journal or magazin.
Sensitization to TLR7 agonist in IFN-beta-preactivated dendritic cells.
Journal of Immunology
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
TLRs interact with a growing list of pathogen-derived products and these interactions drive the activation of innate and adaptive immune responses. Dendritic cells (DC) play a key role in these events expressing a heterogeneous repertoire of TLRs. We have previously demonstrated the production of type I IFNs in DC following bacterial infections and TLR triggering. In this study, we sought to characterize the transcriptome specifically induced in human DC by IFN-beta production stimulated upon LPS treatment. To this aim, by using cDNA microarrays, we compared the transcriptome of DC following LPS treatment in the absence or presence of neutralizing anti-type I IFN Abs. Interestingly, we found that the expression of TLR7 was induced during LPS-induced maturation of DC in a type I IFN-dependent manner. The induction of TLR7 in maturing DC was mainly a consequence of the transcriptional activity of IRF-1, whose binding site was located within TLR7 promoter. Moreover, we also demonstrated that "priming" of immature DC, that usually express TLR8 but not TLR7, with exogenous IFN-beta induced a functionally active TLR7. In fact, treatment with the TLR7-specific ligand 3M-001 up-regulated the expression of CD83, CD86, and CD38 in IFN-beta-primed DC but not in immature DC. Therefore, a robust enhancement in proinflammatory as well as regulatory cytokines was observed. These data suggest that TLR4-mediated type I IFN release activates specific transcription programs in DC amplifying the expression of pathogen sensors to correctly and combinatorially respond to a bacterial as well as viral infection.
Antigens, Surface/biosynthesis, Antigens, Surface/genetics, Cell Differentiation/genetics, Cell Differentiation/immunology, Cells, Cultured, Cytokines/biosynthesis, Cytokines/genetics, Dendritic Cells/cytology, Dendritic Cells/immunology, Gene Expression Profiling, Humans, Immunity, Innate/genetics, Inflammation Mediators/metabolism, Interferon Regulatory Factor-1/physiology, Interferon-beta/physiology, Ligands, Lipopolysaccharides/pharmacology, Toll-Like Receptor 7/agonists, Toll-Like Receptor 7/biosynthesis
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