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Horm Metab Res 2003; 35(8): 466-470
DOI: 10.1055/s-2003-41803
Original Basic
© Georg Thieme Verlag Stuttgart · New York

HMG-CoA Reductase Inhibitor Cerivastatin Inhibits Interleukin-6 Expression and Secretion in Human Adipocytes

V.  van Harmelen1 , T.  Skurk1 , K.  Röhrig1 , H.  Hauner1
  • 1Deutsches Diabetes-Forschungsinstitut, Düsseldorf, Germany
Further Information

Publication History

Received 10 February 2003

Accepted after revision 31 March 2003

Publication Date:
02 September 2003 (online)

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Abstract

Human adipose tissue is a main contributor to plasma levels of pro-inflammatory cytokine IL-6. How IL-6 expression is regulated in adipocytes remains unclear. In the current study, we investigated the effect of the HMG-CoA reductase inhibitor, cerivastatin, on the production of IL-6 from cultured human adipocytes. Cerivastatin reduced both IL-6 mRNA and secretion in a dose- and time-dependent manner. The inhibitory effect on IL-6 mRNA was prevented by the intermediates of the cholesterol synthesis pathway, mevalonate and geranyl-geranyl-phyrophosphate (GGPP) but not by farnesyl-pyrophosphate. This suggests the involvement of geranylgeranyl-modified intermediates in the effect of cerivastatin on IL-6. Moreover, cerivastatin induced an inactivation of the phosphorylation of the p65 subunit of NFκB which was prevented by GGPP. Our data suggest that cerivastatin exerts an anti-inflammatory effect by down-regulating IL-6 levels in adipocytes, which seems to be mediated by reduced production of GGPP and interference with the NFκB pathway.

Key words

Statins - Signalling - Interleukin-6 - NFκB - Isoprenoids - Mevalonate

References

  • 1 Maron D J, Fazio S, Linton M F. Current perspectives on statins.  Circulation. 2000;  101 207-213
    PubMedSearch in Google Scholar
  • 2 Istvan E S, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase.  Science. 2001;  292 1160-1164
    CrossrefPubMedSearch in Google Scholar
  • 3 Liao J K. Isoprenoids as mediators of the biological effects of statins. J. Clin.  Invest. 2002;  110 285-288
    PubMedSearch in Google Scholar
  • 4 Campbell S L, Khosravi-Far R, Rossman K L, Clark G J, Der C J. Increasing complexity of Ras signaling.  Oncogene. 1998;  17 1395-1413
    CrossrefPubMedSearch in Google Scholar
  • 5 Rezaie-Majd A, Maca T, Bucek R A, Valent P, Muller M R, Husslein P, Kashanipour A, Minar E, Baghestanian M. Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients.  Arterioscler Thromb Vasc Biol.. 2002;  22 1194-1199
    PubMedSearch in Google Scholar
  • 6 Ito T, Ikeda U, Shimpo M, Ohki R, Takahashi M, Yamamoto K, Shimada K. HMG-CoA Reductase inhibitors reduce interleukin-6 synthesis in human vascular smooth muscle cells. Cardiovasc.  Drugs Ther. 2002;  16 121-126
    PubMedSearch in Google Scholar
  • 7 Mantovani A, Bussolino F, Introna M. Cytokine regulation of endothelial cell function: from molecular level to the bedside.  Immunol Today. 1997;  18 231-240
    CrossrefPubMedSearch in Google Scholar
  • 8 Libermann T A, Baltimore D. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor.  Mol Cell Biol. 1990;  10 2327-2334
    PubMedSearch in Google Scholar
  • 9 Matsusaka T, Fujikawa K, Nishio Y, Mukaida N, Matsushima K, Kishimoto T, Akira S. Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8.  Proc Natl Acad Sci U S A.. 1993;  90 10 193-10 197
    PubMedSearch in Google Scholar
  • 10 Kim S I, Kim H J, Han D C, Lee H B. Effect of lovastatin on small GTP binding proteins and on TGF-beta1 and fibronectin expression.  Kidney Int Suppl. 2000;  77 S88-92
    PubMedSearch in Google Scholar
  • 11 Yang B C, Wang Y S, Liu H S, Lin S J. Ras signaling is involved in the expression of Fas-L in glioma.  Lab Invest. 2000;  80 529-537
    PubMedSearch in Google Scholar
  • 12 Mohamed-Ali V, Goodrick S, Rawesh A, Katz D R, Miles J M, Yudkin J S, Klein S, Coppack S W. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo.  J Clin Endocrinol Metab. 1997;  82 4196-4200
    CrossrefPubMedSearch in Google Scholar
  • 13 Kern P A, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance.  Am J Physiol Endocrinol Metab. 2001;  280 E745-51
    CrossrefPubMedSearch in Google Scholar
  • 14 Bastard J P, Jardel C, Bruckert E, Blondy P, Capeau J, Laville M, Vidal H, Hainque B. Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss.  J Clin Endocrinol Metab. 2000;  85 3338-3342
    CrossrefPubMedSearch in Google Scholar
  • 15 Hauner H, Skurk T, Wabitsch M. Cultures of human adipose precursor cells.  Methods Mol Biol. 2001;  155 239-247
    PubMedSearch in Google Scholar
  • 16 Skurk T, Lee Y M, Hauner H. Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary culture.  Hypertension. 2001;  37 1336-1340
    CrossrefPubMedSearch in Google Scholar
  • 17 Janke J, Engeli S, Gorzelniak K, Sharma A M. Extraction of total RNA from adipocytes.  Horm Metab Res. 2000;  33 213-215
    Thieme ConnectPubMedSearch in Google Scholar
  • 18 Weis M, Heeschen C, Glassford A J, Cooke J P. Statins have biphasic effects on angiogenesis.  Circulation. 2002;  105 739-745
    CrossrefPubMedSearch in Google Scholar
  • 19 Sakurai H, Chiba H, Miyoshi H, Sugita T, Toriumi W. IkappaB kinases phosphorylate NF-kappaB p65 subunit on serine 536 in the transactivation domain.  J Biol Chem. 1999;  274 30 353-30 356
    PubMedSearch in Google Scholar
  • 20 Chan D C, Watts G F, Barrett P H, Beilin L J, Mori T A. Effect of atorvastatin and fish oil on plasma high-sensitivity C-reactive protein concentrations in individuals with visceral obesity.  Clin Chem. 2002;  48 877-883
    PubMedSearch in Google Scholar
  • 21 Yudkin J S, Kumari M, Humphries S E, Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?.  Atherosclerosis. 2000;  148 209-214
    CrossrefPubMedSearch in Google Scholar

Prof. Dr. H. Hauner

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