Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase

Antonio Rossi, Pankaj Kapahi, Gioacchino Natoli, Takayuki Takahashi, Yi Chen, Michael Karin () and M. Gabriella Santoro
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Antonio Rossi: Institute of Experimental Medicine, Italian National Council of Research, and
Pankaj Kapahi: Laboratory of Gene Regulation and Signal Transduction, University of California San Diego
Gioacchino Natoli: Laboratory of Gene Regulation and Signal Transduction, University of California San Diego
Takayuki Takahashi: Laboratory of Gene Regulation and Signal Transduction, University of California San Diego
Yi Chen: Laboratory of Gene Regulation and Signal Transduction, University of California San Diego
Michael Karin: Laboratory of Gene Regulation and Signal Transduction, University of California San Diego
M. Gabriella Santoro: Institute of Experimental Medicine, Italian National Council of Research, and

Nature, 2000, vol. 403, issue 6765, 103-108

Abstract: Abstract NF-κB is a critical activator of genes involved in inflammation and immunity1,2. Pro-inflammatory cytokines activate the IκB kinase (IKK) complex that phosphorylates the NF-κB inhibitors, triggering their conjugation with ubiquitin and subsequent degradation3,4. 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 PGE5,6. 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 stimuli10,11, our findings explain how cyclopentenone prostaglandins function and can be used to improve the utility of COX2 inhibitors.

Date: 2000
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DOI: 10.1038/47520

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