Toll-like receptor (TLR) recognition of microbial compounds initiates signalling cascades that activate inflammatory and immune-response genes. A recent report in Nature shows that the nuclear protein IκBζ (inhibitor of nuclear factor-κB (NF-κB), ζ; also known as MAIL and INAP) is required for the initiation of transcription of a subset of these genes.
In this study, IκBζ — previously known to be induced in response to interleukin-1 (IL-1) and the TLR4 ligand lipopolysaccharide (LPS) — was shown to be upregulated in cells stimulated through TLR2, TLR5, TLR7 and TLR9. The importance of this was shown by the observation that macrophages from IκBζ-deficient mice were impaired in their ability to produce IL-6 in response to LPS, as well as ligands for other TLRs and IL-1, whereas tumour-necrosis factor (TNF)-mediated IL-6 production was normal. By contrast, these macrophages produced wild-type levels of other inflammatory mediators (TNF and nitric oxide), indicating that IκBζ is specifically required for IL-6 production in response to TLR and IL-1 signals.
Promoter analysis showed that IκBζ overexpression enhanced LPS-induced Il6 promoter activity, and this effect was dependent upon the NF-κB-binding site in the Il6 promoter. This site is bound by the p50 subunit of NF-κB, and after LPS stimulation, IκBζ was also detected at this site, interacting directly with p50. Consistent with the idea that IκBζ exerts its effects through p50, the production of IL-6 in response to TLR and IL-1 signals was impaired in p50-deficient macrophages, and IκBζ overexpression in these cells failed to induce high levels of IL-6 production.
This paper identifies inducible IκBζ as an essential first component of a two-step signalling pathway that elicits IL-6 production in response to TLR and IL-1 signals. The authors initial analysis indicates that other LPS-inducible genes, such as Il12b and Csf2, require IκBζ function, and further studies will provide new insight into the specific pathways that regulate the expression of individual immune-response genes.
ORIGINAL RESEARCH PAPER
Yamamoto, M. et al. Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IκBζ. Nature 430, 218–222 (2004).
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Honey, K. Selective activation. Nat Rev Immunol 4, 580 (2004). https://doi.org/10.1038/nri1426
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DOI: https://doi.org/10.1038/nri1426