Article abstract
Nature Immunology 10, 965 - 972 (2009)
Published online: 9 August 2009 | doi:10.1038/ni.1771
TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis
Tatsukata Kawagoe1,2,6, Osamu Takeuchi1,2,6, Yoshitsugu Takabatake3, Hiroki Kato1,2, Yoshitaka Isaka4, Tohru Tsujimura5 & Shizuo Akira1,2
Abstract
The intensity and duration of immune responses are controlled by many proteins that modulate Toll-like receptor (TLR) signaling. TANK has been linked to positive regulation of the transcription factors IRF3 and NF-
B. Here we demonstrate that TANK is not involved in interferon responses and is a negative regulator of proinflammatory cytokine production induced by TLR signaling. TLR-induced polyubiquitination of the ubiquitin ligase TRAF6 was upregulated in Tank-/- macrophages. Notably, Tank-/- mice spontaneously developed fatal glomerulonephritis owing to deposition of immune complexes. Autoantibody production in Tank-/- mice was abrogated by antibiotic treatment or the absence of interleukin 6 (IL-6) or the adaptor MyD88. Our results demonstrate that constitutive TLR signaling by intestinal commensal microflora is suppressed by TANK.
- Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
- Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
- Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan.
- Department of Pathology, Hyogo College of Medicine, Hyogo, Japan.
- These authors contributed equally to this work.
Correspondence to: Shizuo Akira1,2 e-mail: sakira@biken.osaka-u.ac.jp
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