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

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 KB (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.