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The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation

Nature volume 391, pages 79–82 (1998)Cite this article

Abstract

The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors that is predominantly expressed in adipose tissue, adrenal gland and spleen1,2,3. PPAR-γ has been demonstrated to regulate adipocyte differentiation and glucose homeostasis in response to several structurally distinct compounds, including thiazolidinediones and fibrates3,4,5,6. Naturally occurring compounds such as fatty acids and the prostaglandin D2 metabolite 15-deoxy-Δ12,14prostaglandin J2 (15d-PGJ2) bind to PPAR-γ and stimulate transcription of target genes7,8,9,10. Prostaglandin D2metabolites have not yet been identified in adipose tissue, butaremajor products of arachidonic-acid metabolism in macrophages11, raising the possibility that they might serve as endogenous PPAR-γ ligands in this cell type. Here we show that PPAR-γ is markedly upregulated in activated macrophages and inhibits the expression of the inducible nitric oxide synthase, gelatinase B and scavenger receptor A genes in response to 15d-PGJ2 and synthetic PPAR-γ ligands. PPAR-γ inhibits gene expression in part by antagonizing the activities of the transcription factors AP-1, STAT and NF-κB. These observations suggest that PPAR-γ and locally produced prostaglandin D2 metabolites are involved in the regulation of inflammatory responses, and raise the possibility that synthetic PPAR-γ ligands may be of therapeutic value in human diseases such as atherosclerosis and rheumatoid arthritis in which activated macrophages exert pathogenic effects.

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Figure 1: Macrophage expression of PPAR-γ and inhibition of iNOS and gelatinase B gene expression by 15d-PGJ2.
Figure 2: 15d-PGJ2 inhibits the gelatinase B, SR-A and iNOS promoters in a PPARγ-dependent manner.
Figure 3: iNOS promoter activity is inhibited by prostaglandin D2 metabolites and synthetic PPAR-γ ligands.
Figure 4: 15-dPGJ2 inhibits transcriptional responses mediated by AP-1, Stat1 and NF-κB transcription factors.

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Acknowledgements

We thank C. Archer for assistance with nitrate measurements, and T. Schneiderman for assistance with manuscript preparation. A.C.L. is supported by a Physician Scientist grant from the NIH. C.J.K. is a clinical investigator of the Medical Research Service, Department of Veterans Affairs. C.K.G. is an established investigator of the American Heart Association. These studies were supported by NIH grants to C.J.K. and C.K.G.

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Authors and Affiliations

  1. Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0651, California, USA

    Mercedes Ricote, Andrew C. Li & Christopher K. Glass

  2. Divisions of Cellular and Molecular Medicine, Endocrinology and Metabolism San Diego Veterans Affairs Medical Center, La Jolla, 92161, California, USA

    Mercedes Ricote

  3. Division of Cardiology, San Diego Veterans Affairs Medical Center, La Jolla, 92161, California, USA

    Andrew C. Li

  4. Division of Nephrology and the San Diego Veterans Affairs Medical Center, La Jolla, 92161, California, USA

    Carolyn J. Kelly

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

    Timothy M. Willson

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Correspondence to Christopher K. Glass.

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Ricote, M., Li, A., Willson, T. et al. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature 391, 79–82 (1998). https://doi.org/10.1038/34178

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