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PPAR-γ agonists inhibit production of monocyte inflammatory cytokines

Nature volume 391, pages 82–86 (1998)Cite this article

Abstract

The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a member of the nuclear receptor family of transcription factors, a large and diverse group of proteins that mediate ligand-dependent transcriptional activation and repression1,2. Expression of PPAR-γ is an early and pivotal event in the differentiation of adipocytes3,4,5,6. Several agents that promote differentiation of fibroblast lines into adipocytes have been shown to be PPAR-γ agonists7,8,9,10, including several prostanoids, of which 15-deoxy-Δ12,14-prostaglandin J2 is the most potent8,9, as well as members of a new class of oral antidiabetic agents, the thiazolidinediones7, and a variety of non-steroidal anti-inflammatory drugs (NSAIDs)10. Here we show that PPAR-γ agonists suppress monocyte elaboration of inflammatory cytokines at agonist concentrations similar to those found to be effective for the promotion of adipogenesis. Inhibition of cytokine production may help to explain the incremental therapeutic benefit of NSAIDs observed in the treatment of rheumatoid arthritis at plasma drug concentrations substantially higher than are required to inhibit prostaglandin G/H synthase (cyclooxygenase).

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Figure 1: Effects of prostaglandin metabolites on induction by phorbol ester of inflammatory cytokines in human monocytes.
Figure 2: Effects of troglitazone and 15d-PGJ2 on induction of TNF-α by lipopolysaccharide, phorbol ester and okadaic acid.
Figure 3: Dose-dependent inhibition by troglitazone and 15d-PGJ2 of PMA-induced cytokine synthesis in monocytes prepared from several donors.
Figure 4: NSAIDs that act on PPAR-γ block production of inflammatory cytokines.
Figure 5: Dose-dependent inhibition of TNF-α production elicited by okadaic acid.
Figure 6: PMA-induced TNF-α expression in human monocytes is inhibited by PPAR-γ agonists.
Figure 7: PPAR-γ agonists specifically inhibit TNF-α promoter-regulated gene expression.

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References

  1. Mangelsdorf, D. J. et al. The nuclear receptor superfamily: the second decade. Cell 83, 835–839 (1995).

    Article  CAS  Google Scholar 

  2. Lemberger, T., Desvergne, B. & Wahli, W. Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology. Annu. Rev. Cell Dev. Biol. 12, 335–363 (1996).

    Article  CAS  Google Scholar 

  3. Chawla, A., Schwarz, E. J., Dimaculangan, D. D. & Lazar, M. A. Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology 135, 798–800 (1994).

    Article  CAS  Google Scholar 

  4. Tontonoz, P., Hu, E., Graves, R. A., Budavari, A. I. & Spiegelman, B. M. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 8, 1224–1234 (1994).

    Article  CAS  Google Scholar 

  5. Tontonoz, P., Hu, E. & Spiegelman, B. M. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 79, 1147–1156 (1994).

    Article  CAS  Google Scholar 

  6. Hu, E., Tontonoz, P. & Spiegelman, B. M. Transdifferentiation by myoblasts by the adipogenic transcription factor PPAR gamma and C/EBP alpha. Proc. Natl Acad. Sci. USA 92, 9856–9860 (1995).

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Kliewer, S. A. et al. Aprostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 83, 813–819 (1995).

    Article  CAS  Google Scholar 

  9. Forman, B. M. et al. 15-Deoxy-delta 12,14-porostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 83, 803–812 (1995).

    Article  CAS  Google Scholar 

  10. Lehmann, J. M., Lenhard, J. M., Oliver, B. B., Ringold, G. M. & Kliewer, S. A. Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J. Biol. Chem. 272, 3406–3410 (1997).

    Article  CAS  Google Scholar 

  11. Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).

    Article  ADS  CAS  Google Scholar 

  12. Patton, J. S. et al. Interferons and tumor necrosis factors have similar catabolic effects on 3T3 L1 cells. Proc. Natl Acad. Sci. USA 83, 8313–8317 (1986).

    Article  ADS  CAS  Google Scholar 

  13. Torti, F. M., Torti, S. V., Larrick, J. W. & Ringold, G. M. Modulation of adipocyte differentiation by tumor necrosis factor and transforming growth factor beta. J. Cell Biol. 108, 1105–1113 (1989).

    Article  CAS  Google Scholar 

  14. Marshall, M. K., Doerrler, W., Feingold, K. R. & Grunfeld, C. Leukemia inhibitory factor induces changes in lipid metabolism in cultured adipocytes. Endocrinology 135, 141–147 (1994).

    Article  CAS  Google Scholar 

  15. Berg, M., Fraker, D. L. & Alexander, H. R. Characterization of differentiation factor/leukaemia inhibitory factor effect on lipoprotein lipase activity and mRNA in 3T3-L1 adipocytes. Cytokine 6, 425–432 (1994).

    Article  CAS  Google Scholar 

  16. Lang, C. H., Dobrescu, C. & Bagby, G. J. Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic gluose output. Endocrinology 130, 43–52 (1992).

    Article  CAS  Google Scholar 

  17. Szalkowski, D., White-Carrington, S., Berger, J. & Zhang, B. Antidiabetic thiazolidinediones block the inhibitory effect of tumor necrosis factor-alpha on differentiation, insulin-stimulated glucose uptake, and gene expression in 3T3-L1 cells. Endocrinology 136, 1474–1481 (1995).

    Article  CAS  Google Scholar 

  18. Braissant, O., Foufelle, F., Scotto, C., Dauca, M. & Wahli, W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 137, 354–366 (1996).

    Article  CAS  Google Scholar 

  19. Greene, M. E. et al. Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Express. 4, 281–299 (1995).

    CAS  Google Scholar 

  20. Devchand, P. R. et al. The PPARalpha-leukotriene B4 pathway to inflammation control. Nature 384, 39–43 (1996).

    Article  ADS  CAS  Google Scholar 

  21. Yu, K. et al. Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J. Biol. Chem. 270, 23975–23983 (1995).

    Article  CAS  Google Scholar 

  22. Meade, E. A., Smith, W. L. & DeWitt, D. L. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J. Biol. Chem. 268, 6610–6614 (1993).

    CAS  PubMed  Google Scholar 

  23. Lau, C. S., Morley, K. D. & Belch, J. J. Effects of fish oil supplementation on non-steroidal anti-inflammatory drug requirement in patients with mild rheumatoid arthritis—a double-blind placebo controlled study. Br. J. Rheumatol. 32, 982–989 (1993).

    Article  CAS  Google Scholar 

  24. Feldmann, M., Brennan, F. M. & Maini, R. N. Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14, 397–440 (1996).

    Article  CAS  Google Scholar 

  25. Brennan, F. M. & Feldman, M. Cytokines in autoimmunity. Curr. Opin. Immunol. 8, 872–877 (1996).

    Article  CAS  Google Scholar 

  26. Moreland, L. W. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N. Engl. J. Med. 337, 141–147 (1997).

    Article  CAS  Google Scholar 

  27. McEvoy, G. K. (ed) AHFS 97 Drug Information (American Society of Health-Systems Pharmacists, Bethesda, MD, (1997)).

    Google Scholar 

  28. Firestein, G. S. & Zvaifler, N. J. Anticytokine therapy in rheumatoid arthritis. N. Engl. J. Med. 337, 195–197 (1997).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank T. Gulick for advice, guidance, time and key reagents. This work was supported by a grant from Amgen, Inc., and awards from the NIH. A.T. is a fellow of the Cancer Research Institute.

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  1. Department of Molecular Biology, Massachusetts General Hospital, Boston, 02114, Massachussetts, USA

    Chengyu Jiang, Adrian T. Ting & Brian Seed

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Correspondence to Brian Seed.

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Jiang, C., Ting, A. & Seed, B. PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 391, 82–86 (1998). https://doi.org/10.1038/34184

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