Selective inhibition of NF-kappa B activation by a peptide that blocks the interaction of NEMO with the I kappa B kinase complex

Activation of the transcription factor nuclear factor (NF)-kappa B by proinflammatory stimuli Leads to increased expression of genes involved in inflammation. Activation of NF-kappa B requires the activity of an inhibitor of kappa B (I kappa B)-kinase (IKK) complex containing two kinases (IKK alpha and IKK beta) and the regulatory protein NEMO (NF-kappa B essential modifier). An amino-terminal alpha-helical region of NEMO associated with a carboxyl-terminal segment of IKK alpha and IKK beta 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-kappa B activation and NF-kappa B-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-kappa B activity.