Report

Selective Inhibition of NF-κB Activation by a Peptide That Blocks the Interaction of NEMO with the IκB Kinase Complex

Science  01 Sep 2000:
Vol. 289, Issue 5484, pp. 1550-1554
DOI: 10.1126/science.289.5484.1550

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Abstract

Activation of the transcription factor nuclear factor (NF)–κB by proinflammatory stimuli leads to increased expression of genes involved in inflammation. Activation of NF-κB requires the activity of an inhibitor of κB (IκB)-kinase (IKK) complex containing two kinases (IKKα and IKKβ) and the regulatory protein NEMO (NF-κB essential modifier). An amino-terminal α-helical region of NEMO associated with a carboxyl-terminal segment of IKKα and IKKβ 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-κB activation and NF-κB–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-κB activity.

  • * To whom correspondence should be addressed. E-mail: sankar.ghosh{at}yale.edu

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