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

Science. 2000 Sep 1;289(5484):1550-4. doi: 10.1126/science.289.5484.1550.

Abstract

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.

Publication types

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

MeSH terms

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

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • E-Selectin
  • NF-kappa B
  • Peptides
  • Recombinant Fusion Proteins
  • Protein Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse