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Interferon response induced by Toll-like receptor signaling

Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan, ERATO, Japan Science and Technology Agency, Osaka, Japan

Hiroaki Hemmi

Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

Shizuo Akira

Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan, ERATO, Japan Science and Technology Agency, Osaka, Japan, sakira{at}biken.osaka-u.ac.jp

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-ß 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-ß 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.

Key Words: Toll-like receptor • TBK1 • IKK-i • type I IFN • TRIF

Journal of Endotoxin Research, Vol. 10, No. 4, 252-256 (2004)
DOI: 10.1177/09680519040100040901


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