IMMUNOLOGY The Other Side of IB

IB proteins are best known as inhibitors that keep the transcription factor NF-B in an inactive form in the cytoplasm. However, the protein family contains a more recently identified member, IB, which is localized to the nucleus. Yamamoto et al. now report characterization of IB-deficient mice that reveals a role for IB 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, IB was detected bound to the IL6 promoter in chromatin immunoprecipitation assays. Immunoprecipitation experiments also showed that IB interacted with the NF-B p50 subunit. IB and NF-B appear to work together because IB-induced expression of IL-6 was decreased in cells from mice lacking NF-B1-p50. Expression of IB 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 IB, 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 IB. Nature 430, 218-222 (2004). [Online Journal]