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:

Interleukin-4-dependent production of PPAR-γ ligands in macrophages by 12/15-lipoxygenase

Nature volume 400, pages 378–382 (1999)Cite this article

Abstract

The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-dependent nuclear receptor that has been implicated in the modulation of critical aspects of development and homeostasis, including adipocyte differentiation1, glucose metabolism2,3 and macrophage development and function4,5,6. PPAR-γ is activated by a range of synthetic and naturally occurring substances, including antidiabetic thiazolidinediones2,3, polyunsaturated fatty acids7, 15-deoxy-Δ12,14prostaglandin J2 (refs 8, 9) and components of oxidized low-density lipoprotein, such as 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE)10. However, the identities of endogenous ligands for PPAR-γ and their means of production in vivo have not been established. In monocytes and macrophages, 13-HODE and 15-HETE can be generated from linoleic and arachidonic acids, respectively, by a 12/15-lipoxygenase that is upregulated by the TH2-derived cytokine interleukin-4 (ref. 11). Here we show that interleukin-4 also induces the expression of PPAR-γ and provide evidence that the coordinate induction of PPAR-γ and 12/15-lipoxygenase mediates interleukin-4-dependent transcription of the CD36 gene in macrophages. These findings reveal a physiological role of 12/15-lipoxygenase in the generation of endogenous ligands for PPAR-γ, and suggest a paradigm for the regulation of nuclear receptor function by cytokines.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Regulation of PPAR-γ expression in macrophages by IL-4.
Figure 2: 15-lipoxygenase products of arachidonic acid and linoleic acid metabolism potentiate transcriptional activation of PPAR-γ.
Figure 3: Inhibitors of 15-LO and PPAR-γ block IL-4-dependent expression of CD36 in macrophages.
Figure 4: Induction of CD36 expression by IL-4 is defective in 12/15-LO−/− macrophages.

Similar content being viewed by others

References

  1. Tontonoz, P., Hu, E. & Spiegelman, B. M. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 79, 1147–1156 (1994).

    Article  CAS  Google Scholar 

  2. Lehmann, J. M.et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor-γ (PPARγ). J. Biol. Chem. 270, 12953–12956 (1995).

    Article  CAS  Google Scholar 

  3. Willson, T. M.et al. The structure–activity relationship between peroxisome proliferator-activated receptor γ agonism and the antihyperglycemic activity of thiazolidinediones. J. Med. Chem. 39, 665–668 (1996).

    Article  CAS  Google Scholar 

  4. Tontonoz, P., Nagy, L., Alvarez, J. G. A., Thomazy, V. A. & Evans, R. M. PPARγ promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93, 241–252 (1998).

    Article  CAS  Google Scholar 

  5. 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 

  6. 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 

  7. Kliewer, S. A.et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ. Proc. Natl Acad. Sci. USA 94, 4318–4323 (1997).

    Article  ADS  CAS  Google Scholar 

  8. Kliewer, S. A.et al. Aprostaglandin J2metabolite binds peroxisome prolifator-activated receptorγ and promotes adipocyte differentiation. Cell 83, 813–819 (1995).

    Article  CAS  Google Scholar 

  9. Forman, B. M.et al. 15-Deoxy-Δ12,14-prostaglandin J2is a ligand for the adipocyte determination factor PPARγ. Cell 83, 803–812 (1995).

    Article  CAS  Google Scholar 

  10. Nagy, L., Tontonoz, P., Alvarez, J. G. A., Chen, H. & Evans, R. M. Oxidized LDL regulates macrophage gene expression through ligand activation of PPAR-γ. Cell 93, 229–240 (1998).

    Article  CAS  Google Scholar 

  11. Conrad, D. J., Kuhn, H., Mulkins, M., Highland, E. & Sigal, E. Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase. Proc. Natl Acad. Sci. USA 89, 217–221 (1992).

    Article  ADS  CAS  Google Scholar 

  12. Ricote, M.et al. Expression of the peroxisome proliferator-activated receptor γ (PPARγ) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc. Natl Acad. Sci. USA 95, 7614–7619 (1998).

    Article  ADS  CAS  Google Scholar 

  13. Zhu, Y.et al. Structural organization of mouse peroxisome proliferator-activated receptor γ (mPPAR γ) gene: alternative promoter use and different splicing yield two mPPAR γ isoforms. Proc. Natl Acad. Sci. USA 92, 7921–7925 (1995).

    Article  ADS  CAS  Google Scholar 

  14. Fajas, L., Fruchart, J. C. & Auwerx, J. PPARγ3 mRNA: a distinct PPARγ mRNA subtype transcribed from an independent promoter. FEBS Lett. 438, 55–60 (1998).

    Article  CAS  Google Scholar 

  15. Yamamoto, S. Mammalian lipoxygenases: molecular structure and functions. Biochem. Biophys. Res. Commun. 1128, 117–131 (1992).

    CAS  Google Scholar 

  16. van Leyen, K., Duvoisin, R. M., Engelhardt, H. & Wiedmann, M. Afunction for lipoxygenase in programmed organelle degradation. Nature 395, 392–395 (1998).

    Article  ADS  CAS  Google Scholar 

  17. Rankin, S. M., Parthasarathy, S. & Steinberg, D. Evidence for a dominant role of lipoxygenase(s) in the oxidation of LDL by mouse peritoneal macrophages. J. Lipid Res. 32, 449–456 (1991).

    CAS  PubMed  Google Scholar 

  18. Benz, D. J.et al. Enhanced levels of lipoperoxides in low density lipoproteins incubated with murine fibroblasts expressing high levels of human 15-lipoxygenase. J. Biol. Chem. 270, 5191–5197 (1995).

    Article  CAS  Google Scholar 

  19. Funk, C. D. The molecular biology of mammalian lipoxygenases and the quest for eicosanoid functions using lipoxygenase-deficient mice. Biochim. Biophys. Acta 1304, 65–84 (1996).

    Article  Google Scholar 

  20. Kuhn, H. Biosynthesis, metabolization and biological importance of the primary 15-lipoxygenase metabolites 15-hydro(pero)xy-5Z,8Z,11Z,13E-eicosatetraenoic acid and 13-hydro(pero)xy-9Z,11E-octadecadienoic acid. Prog. Lipid Res. 35, 203–226 (1996).

    Article  ADS  CAS  Google Scholar 

  21. Heydeck, D.et al. Interleukin-4 and -13 induce upregulation of the murine macrophage 12/15-lipoxygenase activity: evidence for the involvement of transcription factor STAT6. Blood 92, 2503–2510 (1998).

    CAS  PubMed  Google Scholar 

  22. Scheidegger, K. J., Butler, S. & Witztum, J. L. Angiotensin II increases macrophage-mediated modification of low density lipoprotein via a lipoxygenase-dependent pathway. J. Biol. Chem. 272, 21609–21615 (1997).

    Article  CAS  Google Scholar 

  23. Bogdan, C., Vodovotz, Y., Paik, J., Xie, Q.-W. & Nathan, C. Mechanism of suppression of nitric oxide synthase expression by interleukin-4 in primary mouse macrophages. J. Leukocyte Biol. 55, 227–233 (1994).

    Article  CAS  Google Scholar 

  24. Yesner, L. M., Huh, H. Y., Pearce, S. F. & Silverstein, R. L. Regulation of monocyte CD36 and thrombospondin-1 expression by soluble mediators. Arterioscler. Thromb. Vasc. Biol. 16, 1019–1025 (1996).

    Article  CAS  Google Scholar 

  25. Yamada, Y., Doi, T., Hamakubo, T. & Kodama, T. Scavenger receptor family proteins: roles for atherosclerosis, host defence and disorders of the central nervous system. Cell. Mol. Life Sci. 54, 628–640 (1998).

    Article  CAS  Google Scholar 

  26. Endemann, G.et al. CD36 is a receptor for oxidized low density lipoprotein. J. Biol. Chem. 268, 11811–11816 (1993).

    CAS  Google Scholar 

  27. Savill, J. S., Hogg, N., Ren, Y. & Haslett, C. Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J. Clin. Invest. 90, 1513–1522 (1992).

    Article  CAS  Google Scholar 

  28. Sun, D. & Funk, C. D. Disruption of 12/15-lipoxygenase expression in peritoneal macrophages. J. Biol. Chem. 271, 24055–24062 (1996).

    Article  CAS  Google Scholar 

  29. Nolte, R. T.et al. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ. Nature 395, 137–143 (1998).

    Article  ADS  CAS  Google Scholar 

  30. Sigal, E. C., Craik, C. S. & Highland, E. Molecular cloning and primary structure of human 15-lipoxygenase. Biochem. Biophys. Res. Commun. 157, 457–464 (1988).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Blanchard (Glaxo Wellcome) for communicating results of the characterization of GW9662 before publication; T. Schneiderman for assistance with manuscript preparation; and J. Barnett for assistance in preparation of human peripheral blood monocytes. J.T.H. is supported by an NIH Postdoctoral Fellowship. J.S.W. is supported by an NIH Medical Scientist Training Program Grant to U. C. San Diego. M.R. is supported by a Postdoctoral Fellowship from the American Heart Association. C.J.K. and D.C. are clinical investigators of the Medical Research Service, Department of Veterans Affairs. C.K.G. is an Established Investigator of the American Heart Association. These studies were also supported by NIH grants to C.D.F. and C.K.G. and a Specialized Center of Research Grant in Atherosclerosis to J.L.W. and C.K.G.

Author information

Author notes

  1. Christopher K. Glass: These authors contributed equally to this work

  2. Christopher K. Glass: Correspondence and requests for materials should be addressed to C.K.G.

Authors and Affiliations

  1. Division of Endocrinology and Metabolism, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0651, California, USA

    Jannet T. Huang, John S. Welch, Mercedes Ricote, Christoph J. Binder, Joseph L. Witztum & Christopher K. Glass

  2. Division of Nephrology, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0651, California, USA

    Jannet T. Huang, John S. Welch & Mercedes Ricote

  3. Division of Pulmonary and Critical Care Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0651, California, USA

    Timothy M. Willson

  4. Division of Cellular and Molecular Medicine, Department and School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0651, California, USA

    Carolyn Kelly

  5. Department of Medicinal Chemistry, Glaxo Wellcome Research and Development, P.O. Box 13398 Research Triangle Park, 27709, North Carolina, USA

    Colin D. Funk

  6. Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Douglas Conrad

Authors
  1. Jannet T. Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John S. Welch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mercedes Ricote
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christoph J. Binder
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Timothy M. Willson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carolyn Kelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Joseph L. Witztum
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Colin D. Funk
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Douglas Conrad
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christopher K. Glass
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher K. Glass.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, J., Welch, J., Ricote, M. et al. Interleukin-4-dependent production of PPAR-γ ligands in macrophages by 12/15-lipoxygenase. Nature 400, 378–382 (1999). https://doi.org/10.1038/22572

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/22572

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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