Interferon response induced by Toll-like receptor signaling.
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-beta 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 proinflammatory 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-beta 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.
Takeuchi
Osamu
O
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Hemmi
Hiroaki
H
Akira
Shizuo
S
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D005347:Fibroblasts; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase; D007371:Interferon-gamma / Q000096:biosynthesis*; D008024:Ligands; D008070:Lipopolysaccharides / Q000633:toxicity; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014162:Transfection
D016207:Cytokines; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D007371:Interferon-gamma; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse