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Natural and Synthetic TLR7 Ligands Inhibit CpG-A- and CpG-C-Oligodeoxynucleotide-Induced IFN- Production¹

Justus-Liebig University, Institute for Clinical Immunology and Transfusion Medicine, Giessen, Germany

Plasmacytoid dendritic cells (pDCs) are unique with respect to their capacity to produce unsurpassed amounts of IFN- and coexpress TLR7 and TLR9, mediating IFN- production. Although TLRs are critical receptors of innate immunity, little is known about the immunological effects of TLR7/TLR9 costimulation. We have analyzed the effects of TLR7/TLR9 costimulation on IFN- production by leukocytes and pDCs. Our experiments revealed that both synthetic (resiquimod and loxoribine) and natural (ssRNA40) TLR7 ligands abrogate CpG-A- and CpG-C-oligodeoxynucleotide (ODN)-induced IFN- production by human leukocytes. Because TLR7 ligands themselves represent important IFN- inducers, we demonstrated that substimulatory TLR7 ligand concentrations significantly inhibited CpG-A-induced IFN-. Delayed addition of TLR7 ligands still resulted in complete suppression of CpG-A-ODN-induced IFN- production, suggesting that the inhibition is unlikely to be caused by a kinetic uptake advantage. Unlike for CpG-A and CpG-C, TLR7 ligands did not inhibit CpG-B-ODN-induced IFN- production. Experiments with purified human pDCs demonstrated that the inhibitory effects of TLR7/TLR9 costimulation were mediated directly by pDCs. Suppression of IFN- production was not related to increased cell death and was also detectable in enriched mouse pDCs. Analyses of pDCs suggested that the TLR7 signal regulates the outcome of TLR7 ligand/CpG-A-ODN costimulation and can either inhibit (IFN-) or promote (IL-8/CD40) cytokine and surface marker expression. Our data reveal for the first time a strong inhibitory effect of TLR7 stimulation on IFN- production induced by CpG-A- and CpG-C-ODNs. These findings provide novel insight into the effects of TLR7/TLR9 costimulation and may support the development of novel TLR9 inhibitors.

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 work was supported by grants from the Bundesministerium für Bildung und Forschung (Germany), Nationales Genomforschungsnetz (NGFN1 IE-S08T03, NGFN2 NIE-S14T30) and by Grant GE-S13T01 (to G.B. and H.H.).

² Address correspondence and reprint requests to Dr. Holger Hackstein, Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig University, Langhansstrasse 7, Giessen, Germany. E-mail address: Holger.Hackstein{at}immunologie.med.uni-giessen.de

³ Abbreviations used in this paper: pDC, plasmacytoid dendritic cell; IRAK, IL-1R-associated kinase; IRF, IFN regulatory factor; ODN, oligodeoxynucleotide; BDCA, blood dendritic cell Ag; DOTAP, N-[1-(2,3-dioeoyloxy)propyl]-N,N,N-trimethylammonium chloride; 7-AAD, 7-aminoactinomycin D; TfR, transferrin receptor; Loxo, loxoribine.