Essential role of nuclear factor (NF)-kappa B-inducing kinase and inhibitor of kappa B (I kappa B) kinase alpha in NF-kappa B activation through lymphotoxin beta receptor, but not through tumor necrosis factor receptor I

Both nuclear factor (NF)-kappaB-inducing kinase (NIK) and inhibitor of kapp aB (I kappaB) kinase (IKK) have been implicated as essential components for NF-kappaB activation in response to many external stimuli. However, the ex act roles of NIK and IKK alpha in cytokine signaling still remain controver sial. With the use of in vivo mouse models, rather than with enforced gene- expression systems, we have investigated the role of NIK and IKK alpha in s ignaling through the type I tamer necrosis factor (TNF) receptor (TNFR-I) a nd the lymphotoxin beta receptor (LT betaR), a receptor essential for lymph oid organogenesis. TNF stimulation induced similar levels of phosphorylatio n and degradation of I kappaB alpha in embryonic fibroblasts from either wi ld-type or NIK-mutant mice. In contrast, LT betaR stimulation induced NF-ka ppaB activation in wild-type mice, but the response was impaired in embryon ic fibroblasts from NIK-mutant and IKK alpha -deficient mice. Consistent wi th the essential role of IKK alpha in LT betaR signaling, we found that dev elopment of Peyer's patches was defective in IKK alpha -deficient mice. The se results demonstrate that both NIK and IKK alpha are essential for the in duction of NF-kappaB through LT betaR, whereas the NIK-IKK alpha pathway is dispensable in TNFR-I signaling.