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TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis.

Kawagoe T, Takeuchi O, Takabatake Y, Kato H, Isaka Y, Tsujimura T, Akira S - Nat. Immunol. (2009)

Bottom Line: 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.Our results demonstrate that constitutive TLR signaling by intestinal commensal microflora is suppressed by TANK.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.

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-kappaB. 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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Antibiotic treatment as well as deficiency of MyD88 or IL-6 ameliorates autoantibody production in Tank−/− mice(a) Anti-dsDNA Abs in sera from 5-month-old Tank−/− (n = 6) and Tank−/−IL-6−/− (n = 6) mice. (b) H&E staining of kidney sections from Tank−/− and Tank−/−IL-6−/− mice. (c,d) Anti-dsDNA Abs in Tank−/− (n = 6) and Tank−/−Tnf−/− (n = 6) mice (c), Tank−/− (n = 6) and Tank−/−MyD88−/− (n = 6) mice (d) were measured by ELISA. (e) Oral treatment with antibiotics reduces the serum anti-dsDNA Ab concentrations in Tank−/− mice. WT (n = 6) and Tank−/− (n = 6) mice were given drinking water containing ampicillin (1 g/L), neomycin (1 g/L), vancomycin (0.5 g/L) and metronidazole (1 g/L) after birth. Control wild-type (n = 6) and Tank−/− (n = 6) mice received untreated drinking water. The serum anti-dsDNA Ab concentrations were measured by ELISA at 16 weeks of age.
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Figure 7: Antibiotic treatment as well as deficiency of MyD88 or IL-6 ameliorates autoantibody production in Tank−/− mice(a) Anti-dsDNA Abs in sera from 5-month-old Tank−/− (n = 6) and Tank−/−IL-6−/− (n = 6) mice. (b) H&E staining of kidney sections from Tank−/− and Tank−/−IL-6−/− mice. (c,d) Anti-dsDNA Abs in Tank−/− (n = 6) and Tank−/−Tnf−/− (n = 6) mice (c), Tank−/− (n = 6) and Tank−/−MyD88−/− (n = 6) mice (d) were measured by ELISA. (e) Oral treatment with antibiotics reduces the serum anti-dsDNA Ab concentrations in Tank−/− mice. WT (n = 6) and Tank−/− (n = 6) mice were given drinking water containing ampicillin (1 g/L), neomycin (1 g/L), vancomycin (0.5 g/L) and metronidazole (1 g/L) after birth. Control wild-type (n = 6) and Tank−/− (n = 6) mice received untreated drinking water. The serum anti-dsDNA Ab concentrations were measured by ELISA at 16 weeks of age.

Mentions: Proinflammatory cytokines play critical roles in the development of autoimmune diseases. Overproduction of IL-6 and TNF in mice results in the development of mesangioproliferative glomerulonephritis and chronic polyarthritis, respectively. To investigate whether IL-6 or TNF is involved in disease pathogenesis in Tank−/− mice, we generated mice lacking IL-6 or TNF on the Tank−/− genetic background. The titers of anti-dsDNA Abs were significantly lower in Tank−/−IL-6−/− than in Tank−/− 5 month old mice (Fig. 7a). Moreover, IL-6 deficiency rescued the glomerulonephritis that developed in Tank−/− mice (Fig. 7b). On the other hand, TNF deficiency did not significantly alter the amount of anti-dsDNA Ab production in Tank−/− mice (Fig. 7c). To examine whether MyD88 deficiency protects against the disease progress, we crossed Tank−/− mice with MyD88−/− mice. The anti-dsDNA Ab titers in 5-month-old Tank−/−MyD88−/− mice were significantly lower than in Tank−/− mice (Fig. 7d), indicating that TLR and/or IL-1R family members are critical for the autoimmunity caused by TANK deficiency. The next question we addressed was how TLR and/or IL-1R signaling was activated to cause IL-6 production. Intestinal microflora has been shown to be involved in the pathogenesis of autoimmune diseases, such as colitis in IL-10-deficient mice. Therefore, we orally treated Tank−/− mice with a combination of antibiotics to clear the intestinal microflora. As shown in Fig. 7e, the antibiotic treatment significantly ameliorated the production of anti-dsDNA Abs, suggesting that continuous stimulation of TLRs by intestinal microflora contributes to the generation of autoantibodies in the absence of TANK.


TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis.

Kawagoe T, Takeuchi O, Takabatake Y, Kato H, Isaka Y, Tsujimura T, Akira S - Nat. Immunol. (2009)

Antibiotic treatment as well as deficiency of MyD88 or IL-6 ameliorates autoantibody production in Tank−/− mice(a) Anti-dsDNA Abs in sera from 5-month-old Tank−/− (n = 6) and Tank−/−IL-6−/− (n = 6) mice. (b) H&E staining of kidney sections from Tank−/− and Tank−/−IL-6−/− mice. (c,d) Anti-dsDNA Abs in Tank−/− (n = 6) and Tank−/−Tnf−/− (n = 6) mice (c), Tank−/− (n = 6) and Tank−/−MyD88−/− (n = 6) mice (d) were measured by ELISA. (e) Oral treatment with antibiotics reduces the serum anti-dsDNA Ab concentrations in Tank−/− mice. WT (n = 6) and Tank−/− (n = 6) mice were given drinking water containing ampicillin (1 g/L), neomycin (1 g/L), vancomycin (0.5 g/L) and metronidazole (1 g/L) after birth. Control wild-type (n = 6) and Tank−/− (n = 6) mice received untreated drinking water. The serum anti-dsDNA Ab concentrations were measured by ELISA at 16 weeks of age.
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Related In: Results  -  Collection

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Figure 7: Antibiotic treatment as well as deficiency of MyD88 or IL-6 ameliorates autoantibody production in Tank−/− mice(a) Anti-dsDNA Abs in sera from 5-month-old Tank−/− (n = 6) and Tank−/−IL-6−/− (n = 6) mice. (b) H&E staining of kidney sections from Tank−/− and Tank−/−IL-6−/− mice. (c,d) Anti-dsDNA Abs in Tank−/− (n = 6) and Tank−/−Tnf−/− (n = 6) mice (c), Tank−/− (n = 6) and Tank−/−MyD88−/− (n = 6) mice (d) were measured by ELISA. (e) Oral treatment with antibiotics reduces the serum anti-dsDNA Ab concentrations in Tank−/− mice. WT (n = 6) and Tank−/− (n = 6) mice were given drinking water containing ampicillin (1 g/L), neomycin (1 g/L), vancomycin (0.5 g/L) and metronidazole (1 g/L) after birth. Control wild-type (n = 6) and Tank−/− (n = 6) mice received untreated drinking water. The serum anti-dsDNA Ab concentrations were measured by ELISA at 16 weeks of age.
Mentions: Proinflammatory cytokines play critical roles in the development of autoimmune diseases. Overproduction of IL-6 and TNF in mice results in the development of mesangioproliferative glomerulonephritis and chronic polyarthritis, respectively. To investigate whether IL-6 or TNF is involved in disease pathogenesis in Tank−/− mice, we generated mice lacking IL-6 or TNF on the Tank−/− genetic background. The titers of anti-dsDNA Abs were significantly lower in Tank−/−IL-6−/− than in Tank−/− 5 month old mice (Fig. 7a). Moreover, IL-6 deficiency rescued the glomerulonephritis that developed in Tank−/− mice (Fig. 7b). On the other hand, TNF deficiency did not significantly alter the amount of anti-dsDNA Ab production in Tank−/− mice (Fig. 7c). To examine whether MyD88 deficiency protects against the disease progress, we crossed Tank−/− mice with MyD88−/− mice. The anti-dsDNA Ab titers in 5-month-old Tank−/−MyD88−/− mice were significantly lower than in Tank−/− mice (Fig. 7d), indicating that TLR and/or IL-1R family members are critical for the autoimmunity caused by TANK deficiency. The next question we addressed was how TLR and/or IL-1R signaling was activated to cause IL-6 production. Intestinal microflora has been shown to be involved in the pathogenesis of autoimmune diseases, such as colitis in IL-10-deficient mice. Therefore, we orally treated Tank−/− mice with a combination of antibiotics to clear the intestinal microflora. As shown in Fig. 7e, the antibiotic treatment significantly ameliorated the production of anti-dsDNA Abs, suggesting that continuous stimulation of TLRs by intestinal microflora contributes to the generation of autoantibodies in the absence of TANK.

Bottom Line: 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.Our results demonstrate that constitutive TLR signaling by intestinal commensal microflora is suppressed by TANK.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.

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-kappaB. 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.

Show MeSH
Related in: MedlinePlus