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-κB. 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.
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Acknowledgements
We thank T. Yasui (Osaka University) for Il6−/− mice and plasmids; colleagues in our laboratories; E. Kamada for secretarial assistance; Y. Fujiwara, M. Kumagai and R. Abe for technical assistance; and S. Sato for discussions. Supported by the Special Coordination Funds of the Japanese Ministry of Education, Culture, Sports, Science and Technology, and grants from the Ministry of Health, Labour and Welfare in Japan, the Global Center of Excellence Program of Japan, and the US National Institutes of Health (P01 AI070167).
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T.K., O.T. and S.A. designed the research and analyzed data; T.K. generated Tank−/− mice and did most of the experiments; Y.T., Y.I. and T.T. did histological examination of kidneys; H.K. provided advice; and T.K., O.T. and S.A. prepared the manuscript.
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Kawagoe, T., Takeuchi, O., Takabatake, Y. et al. TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis. Nat Immunol 10, 965–972 (2009). https://doi.org/10.1038/ni.1771
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DOI: https://doi.org/10.1038/ni.1771
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