Abstract
Objective
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.
Results
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 %.
Conclusions
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.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Kendall MJ, Toescu V. Non-lipid properties of statins. J Clin PharmTher 1999; 24: 3–5.
Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000; 6: 1399–402.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 1998; 391: 82–6.
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.
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.
Rollins BJ. Monocyte chemoattractant protein 1: a potential regulator of monocyte recruitment in inflammatory disease. Mol Med Today 1996; 2: 198–204.
Diaz MN, Frei B, Vita JA, Keaney JF Jr. Antioxidants and atherosclerotic heart disease. N Engl J Med 1997; 337: 408–16.
Nathan CF. Secretory products of macrophages. J Clin Invest 1987; 79: 319–26.
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.
Grip O, Janciauskiene S, Lindgren S. Pravastatin down-regulates inflammatory mediators in human monocytes in vitro. Eur J Pharmacol 2000; 410: 83–92.
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.
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.
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.
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.
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.
Fridovich I. Fundamental aspects of reactive oxygen species, or what's the matter with oxygen? Ann NY Acad Sci 1999; 893: 13–8.
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.
Casey PJ. Protein lipidation in cell signaling. Science 1995; 268: 221–5.
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.
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.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Grip, O., Janciauskiene, S. & Lindgren, S. Atorvastatin activates PPAR-γ and attenuates the inflammatory response in human monocytes. Inflamm Res 51, 58–62 (2002). https://doi.org/10.1007/BF02684000
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02684000