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Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase

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.

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Figure 1: PGA1 inhibits TNFα- and TPA-induced IKK and NF-κB activities.
Figure 2: PGA1 prevents NIK-induced IKK activation and inhibits IKKβ activity.
Figure 3: PGJ2 inhibits IKK activity in vivo and in vitro.
Figure 4: Inhibition of IKK activation through endogenously synthesized PGs (PGD and 15dPGJ2).
Figure 5: Effect of arachidonic acid (AA) and its metabolites on IKK activity in vivo and in vitro.
Figure 6: PGJ2 is a direct inhibitor of IKKβ, whose sensitivity to inhibition is mediated by a cysteine in the activation loop.

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Acknowledgements

We thank L. Feng for useful suggestions and for cPLA2 and COX2 expression vectors. This work was supported by grants from the Italian Ministry of Public Health, II National AIDS Research Project (1999), the CNR Target Project on Biotechnology (G.S.), the NIH and the California Cancer Research Program (M.K.). M.K. is the Frank and Else Schilling American Cancer Society Research Professor. P.K., G.N. and Y.C. were supported by postdoctoral fellowships from the Wellcome Trust, Damon-Runyon Walter-Winchell Cancer Research Fund and the Tobacco Related Disease Research Program, respectively.

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Correspondence to Michael Karin.

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Rossi, A., Kapahi, P., Natoli, G. et al. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase. Nature 403, 103–108 (2000). https://doi.org/10.1038/47520

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