IkappaB-zeta,a new anti-inflammatory nuclear protein induced by lipopolysaccharide,is a negative regulator for nuclear factor-kappaB

Activation of nuclear factor-kappaB (NF-kappaB), a prominent cellular response to bacterial endotoxin or other microbial products, must be strictly regulated because excessive activation leads to overproduction of cytotoxic cytokines that culminates in septic shock. During screening for genes up-regulated upon inflammation, we identified a new member of the IkappaB family proteins with the ankyrin-repeats. This protein, designated IkappaB-zeta, is hardly detectable in resting cells, but is strongly induced upon stimulation by lipopolysaccharide, which stimulates cells through the Toll-like receptor 4. Interleukin-1beta stimulation also results in the strong induction of IkappaB-zeta, but tumor necrosis factor-alpha does not. In contrast to IkappaB-alpha or IkappaB-beta, IkappaB-zeta localizes in the nucleus, where it inhibits NF-kappaB activity. NF-kappaB activity is essential for the induction of IkappaB-zeta, but is not sufficient. Thus, this protein is a new anti-inflammatory protein, which is specifically induced upon inflammation to regulate NF-kappaB activity.