Essential roles for NF-κB and a Toll/IL-1 receptor domain-specific signal(s) in the induction of IκB-ζ

IκB-ζ, a new negative-regulator of nuclear factor-κB (NF-κB), is strongly induced by lipopolysaccharide or interleukin-1β stimulation, but not by tumor necrosis factor-α. Here, we analyzed the mechanisms for transcriptional induction of IκB-ζ. IκB-ζ mRNA was induced by overexpression of MyD88 or TRAF6, but not TRAF2. Stimulation of macrophages with peptidoglycan or CpG DNA, which activated Toll-like receptor 2 or 9, respectively, also resulted in IκB-ζ induction. Thus, activation of the MyD88-dependent signaling pathway, commonly found downstream of different Toll/interleukin-1 receptor (TIR) domains, is sufficient for IκB-ζ induction. The induction was inhibited by treatment with various inhibitors of NF-κB activation or by overexpressing IκB-α or β, indicating essential roles for NF-κB in IκB-ζ induction. However, overexpression of the NF-κB subunits induced IκB-α, but not IκB-ζ. These results indicate the existence of another signal essential for IκB-ζ induction, which is specifically mediated by the TIR domain-mediated signaling pathway.