Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase

Nature volume 403, pages 103–108 (2000)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Baldwin,A. S. The NF-κB and IκB proteins: new discoveries and insights. Annu. Rev. Immunol. 14, 649–683 (1996).

    Article  CAS  Google Scholar 

  2. Barnes,P. J. & Karin,M. Nuclear factor-κB—a pivotal transcription factor in chronic inflammatory diseases. New Engl. J. Med. 336, 1066–1071 (1997).

    CAS  Google Scholar 

  3. DiDonato,J. A., Hayakawa,M., Rothwarf,D. M., Zandi,E. & Karin,M. A cytokine-responsive IκB kinase that activates the transcription factor NF-κB. Nature 388, 548–554 (1997).

    Article  ADS  CAS  Google Scholar 

  4. Zandi,E., Chen,Y. & Karin,M. Direct phosphorylation of IκB by IKKα and IKKβ: discrimination between free and NF-κB-bound substrate. Science 281, 1360–1363 (1998).

    Article  ADS  CAS  Google Scholar 

  5. Herschman,H. R. et al. Function and regulation of prostaglandin synthase-2. Adv. Exp. Med. Biol. 407, 61–66 (1997).

    Article  CAS  Google Scholar 

  6. Newton,R., Kintert,L. M. E., Bergmann,M., Adcock,I. M. & Barnes,P. I. Evidence for involvement of NF-κB in the transcriptional control of COX-2 gene expression by IL-1β. Biochem. Biophys. Res. Comm. 237, 28–32 (1997).

    Article  CAS  Google Scholar 

  7. Gilroy,D. W. et al. Inducible cyclooxygenase may have anti-inflammatory properties. Nature Med. 5, 698–701 (1999).

    Article  CAS  Google Scholar 

  8. Ricote,M., Li,A. C., Willson,T. M., Kelly,C. J. & Glass,C. K. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature 391, 79–82 (1998).

    Article  ADS  CAS  Google Scholar 

  9. Jiang,C., Ting,A. T. & Seed,B. PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 391, 82–86 (1998).

    Article  ADS  CAS  Google Scholar 

  10. Delhase,M., Hayakawa,M., Chen,Y. & Karin,M. Positive and negative regulation of IκB kinase activity through IKKβ subunit phosphorylation. Science 284, 309–313 (1999).

    Article  ADS  CAS  Google Scholar 

  11. Tanaka,M. et al. Embryonic lethality, liver degeneration and impaired NF-κB activation in IKK-β-deficient mice. Immunity 10, 421–429 (1999).

    Article  CAS  Google Scholar 

  12. Santoro,M. G. Antiviral activity of cyclopentenone prostanoids. Trends Microbiol. 5, 276–281 (1997).

    Article  CAS  Google Scholar 

  13. Rozera,C. et al. Inhibition of HIV-1 replication by cyclopentenone prostaglandins in acutely infected human cells. J. Clin. Invest. 97, 1795–1803 (1996).

    Article  CAS  Google Scholar 

  14. Rossi,A., Elia,G. & Santoro,M. G. Inhibition of nuclear factor κB by prostaglandin A1: an effect associated with heat shock transcription factor activation. Proc. Natl Acad. Sci. USA 94, 746–750 (1997).

    Article  ADS  CAS  Google Scholar 

  15. Rothwarf,D. M., Zandi,E., Natoli,G. & Karin,M. IKK-γ is an essential regulatory subunit of the IκB kinase complex. Nature 395, 297–300 (1998).

    Article  ADS  CAS  Google Scholar 

  16. Yamaoka,S. et al. Complementation cloning of NEMO, a component of the IκB kinase complex essential for NF-κB activation. Cell 93, 1231–1240 (1998).

    Article  CAS  Google Scholar 

  17. Karin,M. & Delhase,M. JNK or IKK, AP-1 or NF-κB, which are the targets for MEK kinase 1 action? Proc. Natl Acad. Sci. USA 95, 9067–9069 (1998).

    Article  ADS  CAS  Google Scholar 

  18. Yin,M., Yamamoto,Y. & Gaynor,R. B. The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-β. Nature 398, 77–80 (1998).

    Article  ADS  Google Scholar 

  19. Fukushima,M. Prostaglandin J2-anti-tumor and anti-viral activities and the mechanisms involved. Eicosanoids 3, 189–199 (1990).

    CAS  PubMed  Google Scholar 

  20. Rossi,A., Elia,G. & Santoro,M. G. 2-Cyclopenten-1-one, a new inducer of heat shock protein 70 with antiviral activity. J. Biol. Chem. 271, 32192–32196 (1996).

    Article  CAS  Google Scholar 

  21. Gray,N. S. et al. Exploiting chemical libraries, structure and genomics in the search for kinase inhibitors. Science 281, 533–537 (1998).

    Article  ADS  CAS  Google Scholar 

  22. Santoro,M. G., Garaci,E. & Amici,C. Prostaglandins with antiproliferative activity induce the synthesis of a heat shock protein in human cells. Proc. Natl Acad. Sci. USA 86, 8407–8411 (1989).

    Article  ADS  CAS  Google Scholar 

  23. Santoro,M. G., Benedetto,A., Carruba,G., Garaci,E. & Jaffe,B. M. Prostaglandin A compounds as antiviral agents. Science 209, 1032–1034 (1980).

    Article  ADS  CAS  Google Scholar 

  24. Staels,B. et al. Activation of human aorta smooth-muscle cells is inhibited by PPARα but not by PPARγ activators. Nature 393, 790–793 (1998).

    Article  ADS  CAS  Google Scholar 

  25. Serhan,C. N., Haeggström,J. Z. & Leslie,C. C. Lipid mediator networks in cell signaling: update and impact of cytokines. FASEB J. 10, 1147–1158 (1996).

    Article  CAS  Google Scholar 

  26. Calderwood,S. K., Bornstein,B., Farnum,E. K. & Stevenson,M. A. Heat shock stimulates the release of arachidonic acid and the synthesis of prostaglandins and leukotriene B4 in mammalian cells. J. Cell Physiol. 141, 325–333 (1989).

    Article  CAS  Google Scholar 

  27. Leung,D. Y. et al. Increased in vitro bone resorption by monocytes in the hyper-immunoglobulin E syndrome. J. Immunol. 140, 84–88 (1988).

    CAS  PubMed  Google Scholar 

  28. Offenbacher,S., Odle,B. M. & Van Dyke,T. E. The use of crevicular fluid prostaglandin E2 levels as a predictor of periodontal attachment loss. J. Periodontal Res. 21, 101–112 (1986).

    Article  CAS  Google Scholar 

  29. Wang,C. Y., Mayo,M. W. & Baldwin,A. S. TNF and cancer therapy-induced apoptosis: potentiation by inhibition of NF-κB. Science 274, 786–787 (1998).

    Google Scholar 

  30. Hirose,S. et al. Expression and localization of cyclooxygenase isoforms and cytosolic phospholipase A2 in anti-Thy-1 glomerulonephritis. J. Am. Soc. Nephrol. 9, 408–416 (1998).

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

Author notes

  1. Antonio Rossi, Pankaj Kapahi, Gioacchino Natoli, Michael Karin and M. Gabriella Santoro: These authors contributed equally to this work

Authors and Affiliations

  1. Institute of Experimental Medicine, Italian National Council of Research, and ,

    Antonio Rossi & M. Gabriella Santoro

  2. Laboratory of Virology, Department of Biology, University of Rome Tor Vergata, Rome, 00133, Italy

    M. Gabriella Santoro

  3. Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, University of California San Diego, 9500 Gilman Drive, La Jolla, 92093-0636, California, USA

    Pankaj Kapahi, Gioacchino Natoli, Takayuki Takahashi, Yi Chen & Michael Karin

Authors
  1. Antonio Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pankaj Kapahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gioacchino Natoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takayuki Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Karin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. Gabriella Santoro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Karin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/47520

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing