title: Innate immune responses in human monocyte-derived dendritic cells are highly dependent on the size and the 5' phosphorylation of RNA molecules.
abstract: Recognition of viral genetic material takes place via several different receptor systems, such as retinoic acid-inducible gene I-like receptors and TLRs 3, 7, 8, and 9. At present, systematic comparison of the ability of different types of RNAs to induce innate immune responses in human immune cells has been limited. In this study, we generated bacteriophage 6 and influenza A virus-specific ssRNA and dsRNA molecules ranging from 58 to 2956 nt. In human monocyte-derived dendritic cells (moDCs), short dsRNAs efficiently upregulated the expression of IFN (IFN-α, IFN-β, and IFN-λ1) and proinflammatory (TNF-α, IL-6, IL-12, and CXCL10) cytokine genes. These genes were also induced by ssRNA molecules, but size-specific differences were not as pronounced as with dsRNA molecules. Dephosphorylation of short ssRNA and dsRNA molecules led to a dramatic reduction in their ability to stimulate innate immune responses. Such a difference was not detected for long ssRNAs. RNA-induced cytokine responses correlated well with IFN regulatory factor 3 phosphorylation, suggesting that IFN regulatory factor 3 plays a major role in both ssRNA- and dsRNA-activated responses in human moDCs. We also found that IFN gene expression was efficiently stimulated following recognition of short dsRNAs by retinoic acid-inducible gene I and TLR3 in human embryonic kidney 293 cells, whereas ssRNA-induced responses were less dependent on the size of the RNA molecule. Our data suggest that human moDCs are extremely sensitive in recognizing foreign RNA, and the responses depend on RNA size, form (ssRNA versus dsRNA), and the level of 5' phosphorylation.
authors: National Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors: Miao
authors: M
authors: Jiang
authors: Pamela
authors: P
authors: Osterlund
authors: L Peter
authors: LP
authors: Sarin
authors: Minna M
authors: MM
authors: Poranen
authors: Dennis H
authors: DH
authors: Bamford
authors: Deyin
authors: D
authors: Guo
authors: Ilkka
authors: I
authors: Julkunen
mesh_terms: D017126:Bacteriophage phi 6 / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D009980:Influenza A virus / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000276:immunology; D009000:Monocytes / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D012330:RNA, Double-Stranded / Q000276:immunology* / Q000494:pharmacology; D012367:RNA, Viral / Q000276:immunology* / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000276:immunology; D015534:Trans-Activators; D014157:Transcription Factors / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D016207:Cytokines; D050838:Interferon Regulatory Factor-3; C431552:RAI1 protein, human; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D051193:Toll-Like Receptors; D015534:Trans-Activators; D014157:Transcription Factors