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PMID: 12354379 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

IRF3 mediates a TLR3/TLR4-specific antiviral gene program.

Immunity ·Vol. 17 ·No. 3 ·2002-09-00 ·Pages 251-63

Doyle S, Vaidya S, O'Connell R, Dadgostar H, Dempsey P, Wu T, Rao G, Sun R, Haberland M, Modlin R, Cheng G

Abstract

We have identified a subset of genes that is specifically induced by stimulation of TLR3 or TLR4 but not by TLR2 or TLR9. Further gene expression analyses established that upregulation of several primary response genes was dependent on NF-kappaB, commonly activated by several TLRs, and interferon regulatory factor 3 (IRF3), which was found to confer TLR3/TLR4 specificity. Also identified was a group of secondary response genes which are part of an autocrine/paracrine loop activated by the primary response gene product, interferon beta (IFNbeta). Selective activation of the TLR3/TLR4-IRF3 pathway potently inhibited viral replication. These results suggest that TLR3 and TLR4 have evolutionarily diverged from other TLRs to activate IRF3, which mediates a specific gene program responsible for innate antiviral responses.

MeSH Terms

3T3 Cells Animals Autocrine Communication/genetics Cell Line DNA-Binding Proteins/genetics,physiology Drosophila Proteins Gene Expression Profiling Gene Expression Regulation/physiology Humans I-kappa B Proteins/genetics,physiology Immunity, Innate Interferon Regulatory Factor-3 Interferon-beta/physiology Lipopolysaccharides/pharmacology Macrophages/immunology Membrane Glycoproteins/physiology Mice Mice, Inbred C57BL Models, Immunological NF-kappa B/physiology Paracrine Communication/genetics Peptidoglycan/pharmacology Receptors, Cell Surface/physiology Recombinant Fusion Proteins/physiology Rhadinovirus/physiology Signal Transduction Toll-Like Receptor 2 Toll-Like Receptor 3 Toll-Like Receptor 4 Toll-Like Receptor 9 Toll-Like Receptors Transcription Factors/genetics,physiology Transcription, Genetic Transfection Virus Diseases/immunology Virus Replication

Chemicals

DNA-Binding Proteins Drosophila Proteins I-kappa B Proteins IRF3 protein, human Interferon Regulatory Factor-3 Irf3 protein, mouse Lipopolysaccharides Membrane Glycoproteins NF-kappa B Peptidoglycan Receptors, Cell Surface Recombinant Fusion Proteins TLR2 protein, human TLR3 protein, human TLR4 protein, human TLR9 protein, human Toll-Like Receptor 2 Toll-Like Receptor 3 Toll-Like Receptor 4 Toll-Like Receptor 9 Toll-Like Receptors Transcription Factors Interferon-beta

Authors & Affiliations

11 authors, click to expand affiliations / ORCID

Doyle Sean

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Vaidya Sagar

O'Connell Ryan

Dadgostar Hajir

Dempsey Paul

Wu Ting

Rao Govinda

Sun Ren

Haberland Margaret

Modlin Robert

Cheng Genhong

Article Info

Journal

Immunity

Abbr.

Immunity

ISSN

1074-7613

DOI

10.1016/s1074-7613(02)00390-4

Published

2002-09-00

Pages

251-63

Language

English

Region

United States

NLM ID

9432918

Subset

Grants

NCI NIH HHS · 5-T32-CA009120-26 · United States

NIGMS NIH HHS · GM 08042 · United States

NCI NIH HHS · R01 CA87924 · United States

NIGMS NIH HHS · R01 GM57559 · United States

NIAID NIH HHS · R37 AI47868 · United States

External Links

PubMed source DOI: 10.1016/s1074-7613(02)00390-4 View journal details

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IRF3 mediates a TLR3/TLR4-specific antiviral gene program.

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