Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase

NF-kappa B is a critical activator of genes involved in inflammation and immunity(1,2). Pro-inflammatory cytokines activate the I kappa B kinase (IKK) complex that phosphorylates the NF-kappa B inhibitors, triggering their conjugation with ubiquitin and subsequent degradation(3,4). Freed NF-kappa B 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 inflammation(7). Cyclopentenone prostaglandins have been suggested to exert anti-inflammatory activity through the activation of peroxisome proliferator-activated receptor-gamma (refs 8, 9). Here we demonstrate a novel mechanism of antiinflammatory activity which is based on the direct inhibition and modification of the IKK beta subunit of IKK, As IKK beta is responsible for the activation of NF-kappa B by pro-inflammatory stimuli(10,11), our findings explain how cyclopentenone prostaglandins function and can be used to improve the utility of COX2 inhibitors.