Mechanisms of proinflammatory cytokine-induced biphasic NF-kappaB activation

Mol Cell. 2003 Nov;12(5):1287-300. doi: 10.1016/s1097-2765(03)00390-3.


The transcription factor NF-kappaB regulates genes involved in innate and adaptive immune response, inflammation, apoptosis, and oncogenesis. Proinflammatory cytokines induce the activation of NF-kappaB in both transient and persistent phases. We investigated the mechanism for this biphasic NF-kappaB activation. Our results show that MEKK3 is essential in the regulation of rapid activation of NF-kappaB, whereas MEKK2 is important in controlling the delayed activation of NF-kappaB in response to stimulation with the cytokines TNF-alpha and IL-1alpha. MEKK3 is involved in the formation of the IkappaBalpha:NF-kappaB/IKK complex, whereas MEKK2 participates in assembling the IkappaBbeta:NF-kappaB/IKK complex; these two distinct complexes regulate the proinflammatory cytokine-induced biphasic NF-kappaB activation. Thus, our study reveals a novel mechanism in which different MAP3K and IkappaB isoforms are involved in specific complex formation with IKK and NF-kappaB for regulating the biphasic NF-kappaB activation. These findings provide further insight into the regulation of cytokine-induced specific and temporal gene expression.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • Cells, Cultured
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Gene Expression Regulation*
  • Humans
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Interleukin-1 / metabolism*
  • Isoenzymes / metabolism
  • MAP Kinase Kinase Kinase 2
  • MAP Kinase Kinase Kinase 3
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Mice
  • Multienzyme Complexes
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Protein Structure, Tertiary
  • RNA, Small Interfering
  • Signal Transduction / physiology
  • Tumor Necrosis Factor-alpha / metabolism*


  • I-kappa B Proteins
  • Interleukin-1
  • Isoenzymes
  • Multienzyme Complexes
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • MAP Kinase Kinase Kinase 2
  • MAP Kinase Kinase Kinase 3
  • MAP Kinase Kinase Kinases
  • MAP3K2 protein, human
  • MAP3K3 protein, human
  • Map3k2 protein, mouse
  • Map3k3 protein, mouse