Abstract
Toll-like receptors (TLRs) recognize microbial components and trigger the inflammatory and immune responses against pathogens. IκBζ (also known as MAIL and INAP) is an ankyrin-repeat-containing nuclear protein that is highly homologous to the IκB family member Bcl-3 (refs 1–6). Transcription of IκBζ is rapidly induced by stimulation with TLR ligands and interleukin-1 (IL-1). Here we show that IκBζ is indispensable for the expression of a subset of genes activated in TLR/IL-1R signalling pathways. IκBζ-deficient cells show severe impairment of IL-6 production in response to a variety of TLR ligands as well as IL-1, but not in response to tumour-necrosis factor-α. Endogenous IκBζ specifically associates with the p50 subunit of NF-κB, and is recruited to the NF-κB binding site of the IL-6 promoter on stimulation. Moreover, NF-κB1/p50-deficient mice show responses to TLR/IL-1R ligands similar to those of IκBζ-deficient mice. Endotoxin-induced expression of other genes such as Il12b and Csf2 is also abrogated in IκBζ-deficient macrophages. Given that the lipopolysaccharide-induced transcription of IκBζ occurs earlier than transcription of these genes, some TLR/IL-1R-mediated responses may be regulated in a gene expression process of at least two steps that requires inducible IκBζ.
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References
Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003)
Janeway, C. A. Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002)
O'Neill, L. A. Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases. Curr. Opin. Pharmacol. 3, 396–403 (2003)
Yamazaki, S., Muta, T. & Takeshige, K. A novel IκB protein, IκB-ζ, induced by proinflammatory stimuli, negatively regulates nuclear factor-κB in the nuclei. J. Biol. Chem. 276, 27657–27662 (2001)
Kitamura, H., Kanehira, K., Okita, K., Morimatsu, M. & Saito, M. MAIL, a novel nuclear IκB protein that potentiates LPS-induced IL-6 production. FEBS Lett. 485, 53–56 (2000)
Haruta, H., Kato, A. & Todokoro, K. Isolation of a novel interleukin-1-inducible nuclear protein bearing ankyrin-repeat motifs. J. Biol. Chem. 276, 12485–12488 (2001)
Muzio, M., Ni, J., Feng, P. & Dixit, V. M. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278, 1612–1615 (1997)
Wesche, H., Henzel, W. J., Shillinglaw, W., Li, S. & Cao, Z. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7, 837–847 (1997)
Medzhitov, R. et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol. Cell 2, 253–258 (1998)
Alexopoulou, L., Holt, A. C., Medzhitov, R. & Flavell, R. A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001)
Kawai, T. et al. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J. Immunol. 167, 5887–5894 (2001)
Doyle, S. et al. IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 17, 251–263 (2002)
Ghosh, S. & Karin, M. Missing pieces in the NF-κB puzzle. Cell 109(suppl.), S81–S96 (2002)
Zhang, G. & Ghosh, S. Molecular mechanisms of NF-κB activation induced by bacterial lipopolysaccharide through Toll-like receptors. J. Endotoxin Res. 6, 453–457 (2000)
Janssens, S. & Beyaert, R. Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members. Mol. Cell 11, 293–302 (2003)
Eto, A., Muta, T., Yamazaki, S. & Takeshige, K. Essential roles for NF-κB and a Toll/IL-1 receptor domain-specific signal(s) in the induction of IκB-ζ. Biochem. Biophys. Res. Commun. 301, 495–501 (2003)
Akira, S., Taga, T. & Kishimoto, T. Interleukin-6 in biology and medicine. Adv. Immunol. 54, 1–78 (1993)
Matsusaka, T. et al. Transcription factors NF-IL6 and NF-κB synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc. Natl Acad. Sci. USA 90, 10193–10197 (1993)
Zhong, H., May, M. J., Jimi, E. & Ghosh, S. The phosphorylation status of nuclear NF-κB determines its association with CBP/p300 or HDAC-1. Mol. Cell 9, 625–636 (2002)
Sha, W. C., Liou, H. C., Tuomanen, E. I. & Baltimore, D. Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immune responses. Cell 80, 321–330 (1995)
Sanjabi, S., Hoffmann, A., Liou, H. C., Baltimore, D. & Smale, S. T. Selective requirement for c-Rel during IL-12 P40 gene induction in macrophages. Proc. Natl Acad. Sci. USA 97, 12705–12710 (2000)
Hoffmann, A., Leung, T. H. & Baltimore, D. Genetic analysis of NF-κB/Rel transcription factors defines functional specificities. EMBO J. 22, 5530–5539 (2003)
Hill, M. R. & McCallum, R. E. Identification of tumor necrosis factor as a transcriptional regulator of the phosphoenolpyruvate carboxykinase gene following endotoxin treatment of mice. Infect. Immun. 60, 4040–4050 (1992)
Pasparakis, M. et al. TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417, 861–866 (2002)
Douni, E. et al. Transgenic and knockout analyses of the role of TNF in immune regulation and disease pathogenesis. J. Inflamm. 47, 27–38 (1995)
Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent Toll-Like Receptor signaling pathway. Science 301, 640–643 (2003)
Kinoshita, S., Akira, S. & Kishimoto, T. A member of the C/EBP family, NF-IL6 beta, forms a heterodimer and transcriptionally synergizes with NF-IL6. Proc. Natl Acad. Sci. USA 89, 1473–1476 (1992)
Saitoh, T. et al. TWEAK induces NF-κB2 p100 processing and long lasting NF-κB activation. J. Biol. Chem. 278, 36005–36012 (2003)
Toshchakov, V. et al. TLR4, but not TLR2, mediates IFN-β-induced STAT1α/β-dependent gene expression in macrophages. Nature Immunol. 3, 392–398 (2002)
Kuwata, H. et al. IL-10-inducible Bcl-3 negatively regulates LPS-induced TNF-α production in macrophages. Blood 102, 4123–4129 (2003)
Acknowledgements
We thank T. Kitamura, A. Aderem, D. Golenbock and H. Tomizawa for providing Plat-E packaging cell lines, flagellin, the ELAM1 reporter plasmid, and R-848, respectively. We also thank T. Kawai and K. Ishii for discussions; M. Hashimoto for secretarial assistance; and N. Okita and N. Iwami for technical assistance. This work was supported by grants from Special Coordination Funds, the Ministry of Education, Culture, Sports, Science and Technology, Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists, The Uehara Memorial Foundation, The Naito Foundation, and The Junior Research Associate from RIKEN.
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Supplementary information
Supplementary Discussion 1
Targeted Disruption of murine IκB-ζ gene. (DOC 20 kb)
Supplementary Discussion 2
Relation between the κB sequences of the gene tested and IκB-ζ requirement and regulation of IκB-ζ expression. (DOC 20 kb)
Supplementary Figure 1
Targeted Disruption of murine IκB-ζ gene. (JPG 82 kb)
Supplementary Figure 2
Histological analysis on IκB-ζ-/- mice. (JPG 164 kb)
Supplementary Figure 3
IL-1β-induced activation of signaling cascades IκB-ζ-/- MEFs. (JPG 50 kb)
Supplementary Figure 4a
Gene expression analysis of LPS-inducible genes with statistically selected genes. (JPG 154 kb)
Supplementary Figure 4b-d
Gene expression analysis of LPS-inducible genes with statistically selected genes. (JPG 89 kb)
Supplementary Figure Legends
(DOC 27 kb)
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Yamamoto, M., Yamazaki, S., Uematsu, S. et al. Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IκBζ. Nature 430, 218–222 (2004). https://doi.org/10.1038/nature02738
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DOI: https://doi.org/10.1038/nature02738
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