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Essential Role of Nuclear Factor (NF)-B–inducing Kinase and Inhibitor of B (IB) Kinase in NF-B Activation through Lymphotoxin ß Receptor, but Not through Tumor Necrosis Factor Receptor I

Correspondence to: Mitsuru Matsumoto, Division of Informative Cytology, Institute for Enzyme Research, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. Tel:81-88-633-7432 Fax:81-88-633-7434 E-mail:mitsuru{at}ier.tokushima-u.ac.jp.

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

Key Words: alymphoplasia, cytokine signaling, IB, Akt kinase, Peyer's patch

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