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Originally published in Science Express on 19 February 2004
Science 5 March 2004:
Vol. 303. no. 5663, pp. 1526 - 1529
DOI: 10.1126/science.1093620
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Reports

Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8

Florian Heil,1* Hiroaki Hemmi,2* Hubertus Hochrein,1 Franziska Ampenberger,1 Carsten Kirschning,1 Shizuo Akira,2,3 Grayson Lipford,4 Hermann Wagner,1 Stefan Bauer1{dagger}

Double-stranded ribonucleic acid (dsRNA) serves as a danger signal associated with viral infection and leads to stimulation of innate immune cells. In contrast, the immunostimulatory potential of single-stranded RNA (ssRNA) is poorly understood and innate immune receptors for ssRNA are unknown. We report that guanosine (G)- and uridine (U)-rich ssRNA oligonucleotides derived from human immunodeficiency virus–1 (HIV-1) stimulate dendritic cells (DC) and macrophages to secrete interferon-{alpha} and proinflammatory, as well as regulatory, cytokines. By using Toll-like receptor (TLR)–deficient mice and genetic complementation, we show that murine TLR7 and human TLR8 mediate species-specific recognition of GU-rich ssRNA. These data suggest that ssRNA represents a physiological ligand for TLR7 and TLR8.

1 Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität München, Trogerstr. 9, D - 81675 Munich, Germany.
2 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
3 ERATO, Japan Science and Technology Corporation, Osaka 565-0047, Japan.
4 Coley Pharmaceutical Group, Inc., 93 Worcester Street, Suite 101, Wellesley, MA 02481, USA



* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: stefan.bauer{at}lrz.tum.de

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Suppression of Iodide Uptake and Thyroid Hormone Synthesis with Stimulation of the Type I Interferon System by Double-Stranded Ribonucleic Acid in Cultured Human Thyroid Follicles.
K. Yamazaki, K. Suzuki, E. Yamada, T. Yamada, F. Takeshita, M. Matsumoto, T. Mitsuhashi, T. Obara, K. Takano, and K. Sato (2007)
Endocrinology 148, 3226-3235
   Abstract »    Full Text »    PDF »
Single-Stranded RNA Derived from HIV-1 Serves as a Potent Activator of NK Cells.
G. Alter, T. J. Suscovich, N. Teigen, A. Meier, H. Streeck, C. Brander, and M. Altfeld (2007)
J. Immunol. 178, 7658-7666
   Abstract »    Full Text »    PDF »
TLR Agonists Selectively Promote Terminal Plasma Cell Differentiation of B Cell Subsets Specialized in Thymus-Independent Responses.
L. Genestier, M. Taillardet, P. Mondiere, H. Gheit, C. Bella, and T. Defrance (2007)
J. Immunol. 178, 7779-7786
   Abstract »    Full Text »    PDF »
Chronic Asthma-induced Airway Remodeling Is Prevented by Toll-like Receptor-7/8 Ligand S28463.
P. Camateros, M. Tamaoka, M. Hassan, R. Marino, J. Moisan, D. Marion, M.-C. Guiot, J. G. Martin, and D. Radzioch (2007)
Am. J. Respir. Crit. Care Med. 175, 1241-1249
   Abstract »    Full Text »    PDF »
Functional specialization of human circulating CD16 and CD1c myeloid dendritic-cell subsets.
D. Piccioli, S. Tavarini, E. Borgogni, V. Steri, S. Nuti, C. Sammicheli, M. Bardelli, D. Montagna, F. Locatelli, and A. Wack (2007)
Blood 109, 5371-5379
   Abstract »    Full Text »    PDF »
Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells.
G. Stary, C. Bangert, M. Tauber, R. Strohal, T. Kopp, and G. Stingl (2007)
J. Exp. Med. 204, 1441-1451
   Abstract »    Full Text »    PDF »
Critical role of toll-like receptors and nucleotide oligomerisation domain in the regulation of health and disease.
J. A Mitchell, M. J Paul-Clark, G. W Clarke, S. K McMaster, and N. Cartwright (2007)
J. Endocrinol. 193, 323-330
   Abstract »    Full Text »    PDF »
Poly(I:C) and Lipopolysaccharide Innate Sensing Functions of Circulating Human Myeloid Dendritic Cells Are Affected In Vivo in Hepatitis C Virus-Infected Patients.
I. G. Rodrigue-Gervais, L. Jouan, G. Beaule, D. Sauve, J. Bruneau, B. Willems, R.-P. Sekaly, and D. Lamarre (2007)
J. Virol. 81, 5537-5546
   Abstract »    Full Text »    PDF »
Murine Dendritic Cell Type I IFN Production Induced by Human IgG-RNA Immune Complexes Is IFN Regulatory Factor (IRF)5 and IRF7 Dependent and Is Required for IL-6 Production.
K. Yasuda, C. Richez, J. W. Maciaszek, N. Agrawal, S. Akira, A. Marshak-Rothstein, and I. R. Rifkin (2007)
J. Immunol. 178, 6876-6885
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Leptin-Dependent Toll-Like Receptor Expression and Responsiveness in Preadipocytes and Adipocytes.
A. Batra, J. Pietsch, I. Fedke, R. Glauben, B. Okur, T. Stroh, M. Zeitz, and B. Siegmund (2007)
Am. J. Pathol. 170, 1931-1941
   Abstract »    Full Text »    PDF »
Triggering the Innate Antiviral Response through IRF-3 Activation.
J. Hiscott (2007)
J. Biol. Chem. 282, 15325-15329
   Abstract »    Full Text »    PDF »
Toll-like Receptors and Type I Interferons.
S. Uematsu and S. Akira (2007)
J. Biol. Chem. 282, 15319-15323
   Abstract »    Full Text »    PDF »
Sensitization to TLR7 Agonist in IFN-beta-Preactivated Dendritic Cells.
M. Severa, M. E. Remoli, E. Giacomini, V. Annibali, V. Gafa, R. Lande, M. Tomai, M. Salvetti, and E. M. Coccia (2007)
J. Immunol. 178, 6208-6216
   Abstract »    Full Text »    PDF »
A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity.
T. W. Kim, K. Staschke, K. Bulek, J. Yao, K. Peters, K.-H. Oh, Y. Vandenburg, H. Xiao, W. Qian, T. Hamilton, et al. (2007)
J. Exp. Med. 204, 1025-1036
   Abstract »    Full Text »    PDF »


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