Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IκBζ

Abstract

Toll-like receptors (TLRs) recognize microbial components and trigger the inflammatory and immune responses against pathogens. IkappaBzeta (also known as MAIL and INAP) is an ankyrin-repeat-containing nuclear protein that is highly homologous to the IkappaB family member Bcl-3 (refs 1-6). Transcription of IkappaBzeta is rapidly induced by stimulation with TLR ligands and interleukin-1 (IL-1). Here we show that IkappaBzeta is indispensable for the expression of a subset of genes activated in TLR/IL-1R signalling pathways. IkappaBzeta-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-alpha. Endogenous IkappaBzeta specifically associates with the p50 subunit of NF-kappaB, and is recruited to the NF-kappaB binding site of the IL-6 promoter on stimulation. Moreover, NF-kappaB1/p50-deficient mice show responses to TLR/IL-1R ligands similar to those of IkappaBzeta-deficient mice. Endotoxin-induced expression of other genes such as Il12b and Csf2 is also abrogated in IkappaBzeta-deficient macrophages. Given that the lipopolysaccharide-induced transcription of IkappaBzeta 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 IkappaBzeta.

Enhanced Antibacterial Potential in UBP43-Deficient Mice against Salmonella typhimurium Infection by Up-Regulating Type I IFN Signaling

“…Cytokine and chemokine production during the inflammatory response is regulated by complicated mechanisms. For example, IL-6 expression by LPS has been known to require at least two transcription factors: NF-B and the nuclear protein I B (25,39). Now, our results clearly demonstrated that the type I IFN pathway plays a pivotal role in producing the maximum amount of inflammatory cytokines and chemokines synergistically with other signaling pathways and UBP43 is a crucial component for finishing type I IFN signaling upon LPS challenge.…”

Molecular modeling‐based evaluation of dual function of IκBζ ankyrin repeat domain in toll‐like receptor signaling

“…Recent studies have suggested that the ARD of IkBz can act as either positive (Yamamoto et al, 2004;Motoyama et al, 2005;Trinh et al, 2008) or negative regulators (Totzke et al, 2006) of TLR signaling. The present study was conducted to explain the molecular mechanism of the dual roles played by IkBz with the help of modeling, dynamic simulation, and docking studies of the hetero-and homodimers of NF-kB.…”

“…In mice, there is no expression of IkBz in the resting state and it is induced by lipopolysaccharide (LPS), interleukin-1 beta (IL-b), peptidoglycan, bacterial lipoprotein, flagellin, and C P G DNA, but not by tumor necrosis factor alpha (TNFa) (Yamazaki et al, 2001;Yamamoto et al, 2004;Motoyama et al, 2005). Conversely, human IkBz expression is strongly induced by TNFa (Totzke et al, 2006).…”

Nod1 acts as an intracellular receptor to stimulate chemokine production and neutrophil recruitment in vivo

“…These observations suggest that primary and secondary responses against bacteria in intestinal epithelial cells are diff erent. The genes induced by Nod1, but not TNFα, include TAK1 and Iκ-Bζ, which are critical factors in TLR and IL-1R pathways (27)(28)(29). Co-stimulation with Nod1 and Nod2 enhances TLR signaling (6,30).…”