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Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex.

Activation of the transcription factor nuclear factor (NF)-kappaB by proinflammatory stimuli leads to increased expression of genes involved in inflammation. Activation of NF-kappaB requires the activity of an inhibitor of kappaB (IkappaB)-kinase (IKK) complex containing two kinases (IKKalpha and IKKbeta) and the regulatory protein NEMO (NF-kappaB essential modifier). An amino-terminal alpha-helical region of NEMO associated with a carboxyl-terminal segment of IKKalpha and IKKbeta that we term the NEMO-binding domain (NBD). A cell-permeable NBD peptide blocked association of NEMO with the IKK complex and inhibited cytokine-induced NF-kappaB activation and NF-kappaB-dependent gene expression. The peptide also ameliorated inflammatory responses in two experimental mouse models of acute inflammation. The NBD provides a target for the development of drugs that would block proinflammatory activation of the IKK complex without inhibiting basal NF-kappaB activity.

Pubmed ID: 10968790

Authors

  • May MJ
  • D'Acquisto F
  • Madge LA
  • Gl√∂ckner J
  • Pober JS
  • Ghosh S

Journal

Science (New York, N.Y.)

Publication Data

September 1, 2000

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI 33443

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal
  • COS Cells
  • Cells, Cultured
  • E-Selectin
  • Endothelium, Vascular
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • I-kappa B Kinase
  • Inflammation
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Mutation
  • NF-kappa B
  • Peptides
  • Point Mutation
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases
  • Recombinant Fusion Proteins