TY - JOUR
T1 - Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase
AU - Rossi, Antonio
AU - Kapahi, Pankaj
AU - Natoli, Gloacchino
AU - Takahashi, Takayuki
AU - Chen, Yi
AU - Karin, Michael
AU - Santoro, M. Gabriella
PY - 2000/1/6
Y1 - 2000/1/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0034610759&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034610759&partnerID=8YFLogxK
U2 - 10.1038/47520
DO - 10.1038/47520
M3 - Article
C2 - 10638762
AN - SCOPUS:0034610759
VL - 403
SP - 103
EP - 108
JO - Nature
JF - Nature
SN - 0028-0836
IS - 6765
ER -