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-kB.

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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Contact:

Shizuo Akira
Laboratory of Host Defense,
WPI Immunology Frontier Research Center, Osaka University
3-1 Yamada-oka, Suita City, Osaka 565-0871, Japan

Tel: +81-6-6879-8303, Fax: +81-6-6879-8305
sakira@biken.osaka-u.ac.jp