Journal
NATURE IMMUNOLOGY
Volume 10, Issue 9, Pages 965-U53Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.1771
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Funding
- Japanese Ministry of Education, Culture, Sports, Science and Technology
- Ministry of Health, Labour and Welfare in Japan
- Global Center of Excellence Program of Japan
- US National Institutes of Health [P01 AI070167]
- Grants-in-Aid for Scientific Research [20002008] Funding Source: KAKEN
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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-kappa 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.
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