Editors' ChoiceInflammation

Inhibited Just Enough

Science's STKE  05 Sep 2000:
Vol. 2000, Issue 48, pp. tw4
DOI: 10.1126/stke.2000.48.tw4

The transcription factor NF-κB is a key mediator of the inflammatory response in mammals, and NF-κB inhibitors are of potential therapeutic value. A protein kinase complex containing the two IκB kinases IKKα and IKKβ and the regulatory protein NEMO (or IKKγ) causes activation of NF-κB in response to various inflammatory stimuli. (IκB is an inhibitor of NF-κB, and when IκB is phosphorylated, its inhibition of NF-κB is relieved.) Thus, the IKKs are prime targets for therapeutic intervention, but inhibition of catalytic activity of kinases without affecting other similar enzymes can be difficult (or even harmful, because small amounts of NF-κB protect cells from apoptosis). May et al. found that NEMO interacts with a very small region of the IKKs and that the interaction can be interrupted by a small peptide. When interaction of the IKKs with NEMO is disrupted, activation of NF-κB is effectively inhibited, but the beneficial basal activity of NF-κB is retained. The inhibitory peptide reduced inflammatory responses in two mouse models.

May, M.J., D'Acquisto, F., Madge, L.A., Glöckner, J., Pober, J.S., and Ghosh, S. (2000) Selective inhibition of NF-κB activation by a peptide that blocks the interaction of NEMO with the IκB kinase complex. Science 289: 1550-1554. [Abstract] [Full Text]