15212763

pubmed:Citation

9

Molecular and biochemical analysis indicates that nuclear transcription factor kappaB (NF-kappaB)-inducing kinase (NIK) mediates IKK activation and NF-kappaB transcriptional activity. However, gene deletion studies suggest that NIK triggers gene expression without affecting IkappaBalpha degradation and NF-kappaB DNA binding activity. In order to investigate the role of NIK in NF-kappaB transcriptional activity, we used mouse embryonic fibroblasts (MEF) derived from wild-type (wt) and IkappaB kinase gamma (IKKgamma) gene deficient (IKKgamma(-/-)) mice. We report that although TNF-induced NF-kappaB transcriptional activity is abolished in IKKgamma(-/-) cells, adenoviral gene delivery of NIK (Ad5NIK) still enhanced transcriptional activity and IL-6 mRNA accumulation. Moreover, NIK targets the transactivation function of NF-kappaB through stimulation of the transactivation domain (TAD) of RelA (S536) in IKKgamma(-/-) cells. Interestingly, Ad5NIK, but not TNF, induces RelA S536 and p38 mitogen-activated protein kinase (MAPK) phosphorylation in IKKgamma(-/-) cells. Functional analysis demonstrated that Ad5NIK-induced NF-kappaB transcriptional activity, IL-6 mRNA expression and RelA phosphorylation are inhibited by the p38 inhibitor SB203580, suggesting a role for this MAPK in NIK signaling to NF-kappaB. These data demonstrate for the first time the presence of an IKKgamma-independent NIK/p38 MAPK-dependent signaling pathway that activates NF-kappaB and induces pro-inflammatory gene expression through RelA phosphorylation.

eng

IM

MEDLINE

0898-6568

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NLM

1023-32

pubmed-meshheading:15212763-Animals, pubmed-meshheading:15212763-Cell Line, pubmed-meshheading:15212763-Cell Nucleus, pubmed-meshheading:15212763-Gene Deletion, pubmed-meshheading:15212763-I-kappa B Kinase, pubmed-meshheading:15212763-Interleukin-6, pubmed-meshheading:15212763-Mice, pubmed-meshheading:15212763-Mice, Knockout, pubmed-meshheading:15212763-Mutagenesis, pubmed-meshheading:15212763-NF-kappa B, pubmed-meshheading:15212763-Phosphorylation, pubmed-meshheading:15212763-Protein Transport, pubmed-meshheading:15212763-Protein-Serine-Threonine Kinases, pubmed-meshheading:15212763-RNA, Messenger, pubmed-meshheading:15212763-Transcription Factor RelA, pubmed-meshheading:15212763-Transcriptional Activation, pubmed-meshheading:15212763-Transfection, pubmed-meshheading:15212763-p38 Mitogen-Activated Protein Kinases

NF-kappaB inducing kinase activates NF-kappaB transcriptional activity independently of IkappaB kinase gamma through a p38 MAPK-dependent RelA phosphorylation pathway.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't