IκBNS inhibits induction of a subset of toll-like receptor-dependent genes and limits inflammation

Toll-like receptor (TLR)-mediated immune responses are downregulated by several mechanisms that affect signaling pathways. However, it remains elusive how TLR-mediated gene expression is differentially modulated. Here, we show that I kappa BNS, a TLR-inducible nuclear I kappa B protein, negatively regulates induction of a subset of TLR-dependent genes through inhibition of NF-kappa B activity. I kappa BNS-deficient macrophages and dendritic cells show increased TLR-mediated expression of genes such as IL-6 and IL-12p40, which are induced late after TLR stimulation. In contrast, I kappa BNS-deficient cells showed normal induction of genes that are induced early or induced via IRF-3 activation. LPS stimulation of I kappa BNS-deficient macrophages prolonged NF-kappa B activity at the specific promoters, indicating that I kappa BNS mediates termination of NF-kappa B activity at selective gene promoters. Moreover, I kappa BNS-deficient mice are highly susceptible to LPS-induced endotoxin shock and intestinal inflammation. Thus, I kappa BNS regulates inflammatory responses by inhibiting the induction of a subset of TLR-dependent genes through modulation of NF-kappa B activity.