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* Institute of Clinical Chemistry and Pharmacology, University Hospital, University of Bonn, Bonn, Germany;
Division of Clinical Pharmacology, Department of Internal Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany;
Section Gastroenterology and Endocrinology, Department of Internal Medicine, University of Munich, Munich, Germany; and
Division of Infectious Diseases, Department of Medicine, University of Massachusetts, Worcester, MA 01605
Detection of non-self RNA by TLRs within endosomes and by retinoic acid-inducible gene I (RIG-I)-like helicases in the cytosol is central to mammalian antiviral immunity. In this study, we used pathway-specific agonists and targeted delivery to address RNA immunorecognition in primary human immune cells. Within PBMC, plasmacytoid dendritic cells (pDC) and monocytes were found to be responsible for IFN-
production upon immunorecognition of RNA. The mechanisms of RNA recognition in pDC and monocytes were distinct. In pDC, recognition of ssRNA and dsRNA oligonucleotides was TLR7-dependent, whereas a 5' triphosphate moiety (RIG-I ligand activity) had no major contribution to IFN- production. In monocytes, the response to RNA oligonucleotides was mediated by either TLR8 or RIG-I. TLR8 was responsible for IL-12 induction upon endosomal delivery of ssRNA oligonucleotides and RIG-I was responsible for IFN- production upon delivery of 5' triphosphate RNA into the cytosol. In conclusion, the dissection of these pathways by selecting the appropriate structure and delivery of RNA reveals pDC as major producer of IFN- upon TLR-mediated stimulation and monocytes as major producer of IFN- upon RIG-I-mediated stimulation. Furthermore, our results uncover the potential of monocytes to function as major producers of IL-12p70, a key Th1 cytokine classically ascribed to myeloid dendritic cells that cannot be induced by CpG oligonucleotides in the human system.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by Grants BMBF Biofuture 0311896, SFB 670, SFB 704, KFO115, and KFO 177 to G.H.
2 G.H. and V.H. contributed equally.
3 Address correspondence and reprint requests to Dr. Gunther Hartmann, Institute of Clinical Chemistry and Pharmacology, University Hospital, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. E-mail address: gunther.hartmann{at}uni-bonn.de
4 Abbreviations used in this paper: RIG-1, retinoic acid-inducible gene-I; DC, dendritic cell; HPRT-1, hypoxanthine phosphoribosyltransferase 1; mDC, myeloid DC; MDA5, melanoma differentiation-associated gene 5; nt, nucleotide; ODN, oligodeoxynucleotide; pDC, plasmacytoid DC; pLa, poly-L-arginine; poly(I:C), polyinosinic:polycytidylic acid; siRNA, small interfering RNA; hs, Homo sapiens.
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