Interferon response induced by Toll-like receptor signaling

Abstract

Toll-like receptors (TLRs) are essential for the recognition of distinct pathogen-associated molecular patterns (PAMPs). Activation of TLRs induces intracellular signaling pathways which lead to the production of pro-inflammatory cytokines, chemokines, and interferon (IFN)-inducible genes. TIR domain containing adaptor molecules in turn determine the signaling specificity of the response. Recent studies demonstrated that serine/threonine kinases IKK-i/TBK1 are critical for the regulation of IFN-β as well as IFN-inducible genes. In response to lipopolysaccharide (LPS), transfection of poly(I:C) and viral infection, embryonic fibroblasts (MEFs) derived from TBK1-deficient (TBK1^{— /—} ) mice show impaired production of IFN-inducible genes, but not pro-inflammatory cytokines. Although IKK-i^{— /—} mice show normal production of these genes, MEFs from IKK-i/TBK1-doubly deficient mice were completely defective in the induction of IFN-β as well as IFN-inducible genes in response to poly(I:C) stimulation. Activation of IFN-regulatory factor (IRF) 3 in response to LPS and poly(I:C) was abolished in IKK-i/TBK1 doubly deficient cells. Interestingly, intracellular transduction of poly(I:C) initiates activation of IFN response in a TLR3-independent manner. These observations demonstrate that IKK-i/TBK1 signaling is essential for both TLR3-dependent and TLR3-independent viral and dsRNA-induced IFN responses.

Keywords

Toll-like receptor TBK1 IKK-i type I IFN TRIF

References

Takeda K. , Kaisho T. , Akira S. Toll-like receptors. Annu Rev Immunol 2003 ; 21: 335—376.

Kopp E. , Medzhitov R. Recognition of microbial infection by Toll-like receptors. Curr Opin Immunol 2003; 15: 396—401.

Alexopoulou L. , Holt AC , Medzhitov R. , Flavell RA Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001; 413: 732—738.

Heil F. , Hemmi H. , Hochrein H. et al. Species-specific recognition of single-stranded RNA via Toll-like receptors 7 and 8. Science 2004; 303: 1526—1529.

Diebold SS , Kaisho T. , Hemmi H. , Akira S. , Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 2004; 303: 1529—1531.

Zhang D. , Zhang G. , Hayden MS et al. A Toll-like receptor that prevents infection by uropathogenic bacteria. Science 2004; 303: 1522—1526.

Yamamoto M. , Sato S. , Hemmi H. et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 2002; 420: 324—329.

Kawai T. , Adachi O. , Ogawa T. , Takeda K. , Akira S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 1999; 11: 115—122.

Yamamoto M. , Sato S. , Hemmi H. et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 2003; 301: 640—643.

10.

Hoebe K. , Du X. , Georgel P. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 2003; 424: 743—748.

11.

Sato S. , Sugiyama M. , Yamamoto M. et al. Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J Immunol 2003; 171: 4304—4310.

12.

Meylan E. , Burns K. , Hofmann K. et al. RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappaB activation. Nat Immunol 2004; 5: 503—507.

13.

Yamamoto M. , Sato S. , Hemmi H. et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 2003; 4: 1144—1150.

14.

Sato M. , Suemori H. , Hata N. et al. Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFNalpha/beta gene induction. Immunity 2000; 13: 539—548.

15.

Kawai T. , Takeuchi O. , Fujita T. et al. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol 2001; 167: 5887—5894.

16.

Doyle S. , Vaidya S. , O'Connell R. et al. IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 2002; 17: 251—263.

17.

Toshchakov V. , Jones BW , Perera PY et al. TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. Nat Immunol 2002; 3: 392—398.

18.

Sakaguchi S. , Negishi H. , Asagiri M. et al. Essential role of IRF-3 in lipopolysaccharide-induced interferon-beta gene expression and endotoxin shock. Biochem Biophys Res Commun 2003; 306: 860—866.

19.

Sharma S. , tenOever BR , Grandvaux N. , Zhou GP , Lin R. , Hiscott J. Triggering the interferon antiviral response through an IKK-related pathway . Science 2003; 300: 1148—1151.

20.

Fitzgerald KA , McWhirter SM , Faia KL et al. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 2003; 4: 491—496.

21.

Bonnard M. , Mirtsos C. , Suzuki S. et al. Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription. EMBO J 2000; 19: 4976—4985.

22.

Hemmi H. , Takeuchi O. , Sato S. et al. The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J Exp Med 2004; 199: 1641—1650.

23.

McWhirter SM , Fitzgerald KA , Rosains J. , Rowe DC , Golenbock DT , Maniatis T. IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts. Proc Natl Acad Sci USA 2004; 101: 233—238.

24.

Perry AK , Chow EK , Goodnough JB , Yeh WC , Cheng G. Differential requirement for TANK-binding kinase-1 in type I interferon responses to Toll-like receptor activation and viral infection. J Exp Med 2004; 199: 1651—1658.