Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase

Abstract

NF-κB is a critical activator of genes involved in inflammation and immunity^1,2. Pro-inflammatory cytokines activate the IκB kinase (IKK) complex that phosphorylates the NF-κB inhibitors, triggering their conjugation with ubiquitin and subsequent degradation^3,4. 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^5,6. At late stages of inflammatory episodes, however, COX2 directs the synthesis of anti-inflammatory cyclopentenone prostaglandins, suggesting a role for these molecules in the resolution of inflammation⁷. 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 anti-inflammatory 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^10,11, our findings explain how cyclopentenone prostaglandins function and can be used to improve the utility of COX2 inhibitors.