IκB proteins are best known as inhibitors that keep the transcription factor NF-κB in an inactive form in the cytoplasm. However, the protein family contains a more recently identified member, IκBξ, which is localized to the nucleus. Yamamoto et al. now report characterization of IκBξ-deficient mice that reveals a role for IκBξ in promoting increased expression of specific genes in response to Toll-like receptors (TLRs) and the interleukin 1 receptor (IL-1R). Expression of the gene encoding IL-6 (interleukin 6), normally enhanced in cells after activation of TLRs or IL-1Rs, was unaffected by such stimuli in peritoneal macrophages from the knockout animals. In cells stimulated with lipopolysaccharide to activate TLRs, IκBξ was detected bound to the IL6 promoter in chromatin immunoprecipitation assays. Immunoprecipitation experiments also showed that IκBξ interacted with the NF-κB p50 subunit. IκBξ and NF-κB appear to work together because IκBξ-induced expression of IL-6 was decreased in cells from mice lacking NF-κB1-p50. Expression of IκBξ itself is increased by TLR stimulation with more rapid kinetics than the stimulation of IL-6 and other genes. The authors propose that gene expression initiated by TLRs and IL-1Rs may be a two-step process that requires initial enhancement of expression of IκBξ, which in turn promotes expression of later-responding genes.
M. Yamamoto, S. Yamazaki, S. Uematsu, S. Sato, H. Hemmi, K. Hoshino, T. Kaisho, H. Kuwata, O. Takeuchi, K. Takeshige, T. Saitoh, S. Yamaoka, N. Yamamoto, S. Yamamoto, T. Muta, K. Takeda, S. Akira, Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IκBξ. Nature 430, 218-222 (2004). [Online Journal]