Essential role of nuclear factor (NF)-κB-inducing kinase and inhibitor of κB (IκB) kinase α in NF-κB activation through lymphotoxin β receptor, but not through tumor necrosis factor receptor I

Both nuclear factor (NF)-kappaB-inducing kinase (NIK) and inhibitor of kappaB (I kappaB) kinase (IKK) have been implicated as essential components for NF-kappaB activation in response to many external stimuli. However, the exact roles of NIK and IKK alpha in cytokine signaling still remain controversial. 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 signaling through the type I tamer necrosis factor (TNF) receptor (TNFR-I) and the lymphotoxin beta receptor (LT betaR), a receptor essential for lymphoid organogenesis. TNF stimulation induced similar levels of phosphorylation and degradation of I kappaB alpha in embryonic fibroblasts from either wild-type or NIK-mutant mice. In contrast, LT betaR stimulation induced NF-kappaB activation in wild-type mice, but the response was impaired in embryonic fibroblasts from NIK-mutant and IKK alpha -deficient mice. Consistent with the essential role of IKK alpha in LT betaR signaling, we found that development of Peyer's patches was defective in IKK alpha -deficient mice. These results demonstrate that both NIK and IKK alpha are essential for the induction of NF-kappaB through LT betaR, whereas the NIK-IKK alpha pathway is dispensable in TNFR-I signaling.