Inflammation Research

, Volume 51, Issue 2, pp 58–62 | Cite as

Atorvastatin activates PPAR-γ and attenuates the inflammatory response in human monocytes

  • O. GripEmail author
  • S. Janciauskiene
  • S. Lindgren
Diary Original Research Papers



To investigate the ability of statins to activate the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) in primary human monocytes in culture.

Materials and methods

Human peripheral monocytes were incubated with atorvastatin (0.1–10 μmol/l) for up to 24 hours. PPAR-γ expression was analysed by electrophoretic mobility shift assay. Pro-inflammatory cytokines were measured by enzyme-linked immunosorbent assays, and oxygen consumption was determined polarographically with a Clark-type oxygen electrode.


We found that atorvastatin activates PPAR-γ and inhibits the production of tumour necrosis factor-alpha up to 38% (p < 0.05), monocyte chemoattractant protein-1 up to 85% (p < 0.05), and gelatinase B up to 73% (p < 0.05), in a concentration-dependent manner. Moreover, atorvastatin shows concentration-dependent inhibition of cellular oxygen consumption up to 41 %.


These findings contribute to the growing knowledge of the anti-inflammatory effects of statins, and have led us to the suggestion that statins may control inflammatory responses by the regulation of intracellular lipid homeostasis.

Key words

Atorvastatin Monocytes Inflammation PPAR-γ 


  1. [1]
    Kendall MJ, Toescu V. Non-lipid properties of statins. J Clin PharmTher 1999; 24: 3–5.Google Scholar
  2. [2]
    Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000; 6: 1399–402.PubMedCrossRefGoogle Scholar
  3. [3]
    Sparrow CP, Burton CA, Hernandez M, Mundt S, Hassing H, Patel S et al. Simvastatin has anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering. Arterioscler Thromb Vasc Biol 2001 ; 21: 115–21.PubMedGoogle Scholar
  4. [4]
    Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther 1999; 84: 413–28.PubMedCrossRefGoogle Scholar
  5. [5]
    Ma PT, Gil G, Sudhof TC, Bilheimer DW, Goldstein JL, Brown MS. Mevinolin, an inhibitor of cholesterol synthesis, induces mRNA for low-density lipoprotein receptor in livers of hamsters and rabbits. Proc Natl Acad Sci USA 1986; 83: 8370–4.PubMedCrossRefGoogle Scholar
  6. [6]
    Weber C, Erl W, Weber KS, Weber PC. HMG-CoA reductase inhibitors decrease CD11b expression and CD lib-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol 1997; 30: 1212–7.PubMedCrossRefGoogle Scholar
  7. [7]
    Bocan TM, Mazur MJ, Mueller SB, Brown EQ, Sliskovic DR, O'Brien PM et al. Antiatherosclerotic activity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cholesterolfed rabbits: a biochemical and morphological evaluation. Atherosclerosis 1994; 111: 127–42.PubMedCrossRefGoogle Scholar
  8. [8]
    Hashimoto S, Suzuki T, Dong HY, Yamazaki N, Matsushima K. Serial analysis of gene expression in human monocytes and macrophages. Blood 1999; 94: 837–44.PubMedGoogle Scholar
  9. [9]
    Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K et al. The nuclear receptor superfamily: the second decade. Cell 1995; 83: 835–9.PubMedCrossRefGoogle Scholar
  10. [10]
    Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 1992; 358: 771–4.PubMedCrossRefGoogle Scholar
  11. [11]
    Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM. PPAR-gamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 1998; 93: 241–52.PubMedCrossRefGoogle Scholar
  12. [12]
    Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 1998; 391: 79–82.PubMedCrossRefGoogle Scholar
  13. [13]
    Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 1998; 391: 82–6.PubMedCrossRefGoogle Scholar
  14. [14]
    Chawla A, Boisvert WA, Lee C, Laffitte BA, Barak Y, Joseph SB et al. A PPAR-gamma-LXR-ABCAl Pathway in Macrophages Is Involved in Cholesterol Efflux and Atherogenesis. Mol Cell 2001 ; 7: 161–71.PubMedCrossRefGoogle Scholar
  15. [15]
    Chinetti G, Lestavel S, Bocher V, Remaley AT, Neve B, Torra IP et al. PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med 2001; 7: 53–8.PubMedCrossRefGoogle Scholar
  16. [16]
    Rollins BJ. Monocyte chemoattractant protein 1: a potential regulator of monocyte recruitment in inflammatory disease. Mol Med Today 1996; 2: 198–204.PubMedCrossRefGoogle Scholar
  17. [17]
    Diaz MN, Frei B, Vita JA, Keaney JF Jr. Antioxidants and atherosclerotic heart disease. N Engl J Med 1997; 337: 408–16.PubMedCrossRefGoogle Scholar
  18. [18]
    Nathan CF. Secretory products of macrophages. J Clin Invest 1987; 79: 319–26.PubMedGoogle Scholar
  19. [19]
    Ortego M, Bustos C, Hernandez-Presa MA, Tunon J, Diaz C, Hernandez G et al. Atorvastatin reduces NF-κB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells. Atherosclerosis 1999; 147: 253–61.PubMedCrossRefGoogle Scholar
  20. [20]
    Grip O, Janciauskiene S, Lindgren S. Pravastatin down-regulates inflammatory mediators in human monocytes in vitro. Eur J Pharmacol 2000; 410: 83–92.PubMedCrossRefGoogle Scholar
  21. [21]
    Dichtl W, Moraga F, Ares MP, Crisby M, Nilsson J, Lindgren S et al. The carboxyl-terminal fragment of alpha 1 -antitrypsin is present in atherosclerotic plaques and regulates inflammatory transcription factors in primary human monocytes. Mol Cell Biol Res Commun 2000; 4: 50–61.PubMedCrossRefGoogle Scholar
  22. [22]
    Welgus HG, Campbell EJ, Cury JD, Eisen AZ, Senior RM, Wilhelm SM et al. Neutral metalloproteinases produced by human mononuclear phagocytes. Enzyme profile, regulation, and expression during cellular development. J Clin Invest 1990; 86: 1496–502.PubMedCrossRefGoogle Scholar
  23. [23]
    Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd Z et al. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem 1998; 273: 25573–80.PubMedCrossRefGoogle Scholar
  24. [24]
    Wei YH, Lu CY, Lee HC, Pang CY, Ma YS. Oxidative damage and mutation to mitochondrial DNA and age-dependent decline of mitochondrial respiratory function. Ann NY Acad Sci 1998; 854: 155–70.PubMedCrossRefGoogle Scholar
  25. [25]
    Morel F, Doussiere J, Vignais PV. The superoxide-generating oxidase of phagocytic cells. Physiological, molecular and pathological aspects. Eur J Biochem 1991; 201: 523–46.PubMedCrossRefGoogle Scholar
  26. [26]
    Fridovich I. Fundamental aspects of reactive oxygen species, or what's the matter with oxygen? Ann NY Acad Sci 1999; 893: 13–8.PubMedCrossRefGoogle Scholar
  27. [27]
    Inoue I, Goto S, Mizotani K, Awata T, Mastunaga T, Kawai S et al. Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: reduction of mRNA levels for interleukin-lbeta, interleukin-6, cyclooxygenase-2, and p22phox by regulation of peroxisome proliferator-activated receptor alpha (PPAR-alpha) in primary endothelial cells. Life Sci 2000; 67: 863–76.PubMedCrossRefGoogle Scholar
  28. [28]
    Casey PJ. Protein lipidation in cell signaling. Science 1995; 268: 221–5.PubMedCrossRefGoogle Scholar
  29. [29]
    Tanaka T, Itoh H, Doi K, Fukunaga Y, Hosoda K, Shintani M et al. Down regulation of peroxisome proliferator-activated receptorgamma expression by inflammatory cytokines and its reversal by thiazolidinediones. Diabetologia 1999; 42: 702–10.PubMedCrossRefGoogle Scholar
  30. [30]
    Huang JT, Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C et al. Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature 1999; 400: 378–82.PubMedCrossRefGoogle Scholar
  31. [31]
    Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM. PPAR-gamma dependent and independent effects on macrophagegene expression in lipid metabolism and inflammation. Nat Med 2001; 7: 48–52.PubMedCrossRefGoogle Scholar
  32. [32]
    Thieringer R, Fenyk-Melody JE, Le Grand CB, Shelton BA, Det-mers PA, Somers EP et al. Activation of peroxisome proliferator-activated receptor gamma does not inhibit IL-6 or TNF-alpha responses of macrophages to lipopolysaccharide in vitro or in vivo. J Immunol 2000; 164: 1046–54.PubMedGoogle Scholar
  33. [33]
    Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR-gamma. Cell 1995; 83: 803–12.PubMedCrossRefGoogle Scholar
  34. [34]
    Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 1995; 83: 813–9.PubMedCrossRefGoogle Scholar
  35. [35]
    Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM. Oxidized LDL regulates macrophage gene expression through ligand activation of PPAR-gamma. Cell 1998; 93: 229–40.PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag 2002

Authors and Affiliations

  1. 1.Department of Medicine, Gastroenterology and Hepatology DivisionLund University, University Hospital MASMalmöSweden

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