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

IkappaB-zeta a new negative-regulator of nuclear factor-kappaB (NF-kappaB), is strongly induced by lipopolysaccharide or interleukin-1beta stimulation, but not by tumor necrosis factor-alpha. Here, we analyzed the mechanisms for transcriptional induction of IkappaB-zeta. IkappaB-zeta 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 IkappaB-zeta induction. Thus, activation of the MyD88-dependent signaling pathway, commonly found downstream of different Toll/interleukin-1 receptor (TIR) domains, is sufficient for IkappaB-zeta induction. The induction was inhibited by treatment with various inhibitors of NF-kappaB activation or by overexpressing IkappaB-alpha or P, indicating essential roles for NF-kappaB in IkappaB-zeta induction. However, overexpression of the NF-kappaB subunits induced IkappaB-alpha, but not IkappaB-zeta. These results indicate the existence of another signal essential for IkappaB-zeta induction, which is specifically mediated by the TIR domain-mediated signaling pathway. (C) 2003 Elsevier Science (USA). All rights reserved.