Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway
Masahiro Yamamoto,1
Shintaro Sato,1,2
Hiroaki Hemmi,1
Katsuaki Hoshino,1,4
Tsuneyasu Kaisho,1,4
Hideki Sanjo,1
Osamu Takeuchi,1
Masanaka Sugiyama,1
Masaru Okabe,3
Kiyoshi Takeda,1,2
Shizuo Akira1,2*
Stimulation of Toll-like receptors (TLRs) triggers activation of a common MyD88-dependent signaling pathway as well as a MyD88-independent pathway that is unique to TLR3 and TLR4 signaling pathways leading to interferon (IFN)-ß production. Here we disrupted the gene encoding a Toll/IL-1 receptor (TIR) domain-containing adaptor, TRIF. TRIF-deficient mice were defective in both TLR3- and TLR4-mediated expression of IFN-ß and activation of IRF-3. Furthermore, inflammatory cytokine production in response to the TLR4 ligand, but not to other TLR ligands, was severely impaired in TRIF-deficient macrophages. Mice deficient in both MyD88 and TRIF showed complete loss of nuclear factor kappa B activation in response to TLR4 stimulation. These findings demonstrate that TRIF is essential for TLR3- and TLR4-mediated signaling pathways facilitating mammalian antiviral host defense.
1 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita Osaka 565-0871, Japan.
2 ERATO, Japan Science and Technology Corporation, 3-1 Yamada-oka, Suita Osaka 565-0871, Japan.
3 Genome Information Research Center, 3-1 Yamada-oka, Suita Osaka 565-0871, Japan.
4 RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumiku, Yokohama, Kanagawa 230-0045, Japan
* To whom correspondence should be addressed. E-mail: sakira{at}biken.osaka-u.ac.jp
