Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase

Antonio Rossi, Pankaj Kapahi, Gloacchino Natoli, Takayuki Takahashi, Yi Chen, Michael Karin, M. Gabriella Santoro

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Abstract

NF-κB is a critical activator of genes involved in inflammation and immunity. Pro-inflammatory cytokines activate the IκB kinase (IKK) complex that phosphorylates the NF-κB inhibitors, triggering their conjugation with ubiquitin and subsequent degradation. Freed NF-κB dimers translocate to the nucleus and induce target genes, including the one for cyclo-oxygenase 2 (COX2), which catalyses the synthesis of pro-inflammatory prostaglandins, in particular PGE. At late stages of inflammatory episodes, however, COX2 directs the synthesis of anti-inflammatory cyclopentenone prostaglandins, suggesting a role for these molecules in the revolution of inflammation. Cyclopentenone prostaglandins have been suggested to exert anti-inflammatory activity through the activation of peroxisome proliferator-activated receptor-γ (refs 8, 9). Here we demonstrate a novel mechanism of antiinflammatory activity which is based on the direct inhibition and modification of the IKKβ subunit of IKK. As IKKβ is responsible for the activation of NF-κB by pro-inflammatory stimuli, our findings explain how cyclopentenone prostaglandins function and can be used to improve the utility of COX2 inhibitors.

Original languageEnglish
Pages (from-to)103-108
Number of pages6
JournalNature
Volume403
Issue number6765
DOIs
Publication statusPublished - Jan 6 2000

ASJC Scopus subject areas

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    Rossi, A., Kapahi, P., Natoli, G., Takahashi, T., Chen, Y., Karin, M., & Santoro, M. G. (2000). Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase. Nature, 403(6765), 103-108. https://doi.org/10.1038/47520