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Simvastatin stimulates macrophage interleukin-1beta secretion through an isoprenylation-dependent mechanism.

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Author

Summary, in English

Statin treatment inhibits oxidized lipoprotein-induced intracellular lipid accumulation (foam cell formation) and reduces plasma levels of inflammatory markers such as interleukin-1 beta The aim of the present study was to determine if simvastatin affected lipid accumulation in macrophages incubated with aggregated low density lipoproteins (AgLDL) and whether simvastatin had a direct effect on cytokine secretion from macrophages. Simvastatin treatment did not inhibit AgLDL-induced macrophage lipid accumulation, but significantly increased the secretion of IL-1 beta and IL-8 from macrophages, whilst inhibiting the secretion of tumor necrosis factor-alpha (TNF-alpha) and having no significant effect on IL-6 secretion. Increased macrophage lipid content did not block statin-induced and IL-8 secretion. Simvastatin-stimulated IL-1 beta secretion from macrophages was inhibited by isoprenoids. We therefore hypothesized that simvastatin stimulated IL-1 beta secretion by affecting isoprenylation-dependent signaling pathways. Another possible mechanism for affecting such signaling is to impair isoprenoid transfer protein activity with specific inhibitors such as GGT1-297 and FTInhI. This treatment resulted in strong stimulation of IL-1 beta secretion that was further enhanced when exogenous IL-1 beta was present at the beginning of treatment. These data suggest an isoprenylation-dependent negative-feedback loop for macrophage IL-1 beta secretion that is inhibited by statin treatment. (c) 2006 Elsevier Inc. All rights reserved.

Publishing year

2007

Language

English

Pages

91-96

Publication/Series

Vascular Pharmacology

Volume

46

Issue

Jul 25

Document type

Journal article

Publisher

Elsevier

Topic

  • Cardiac and Cardiovascular Systems

Keywords

  • lipid
  • statin
  • interleukin
  • isoprenylation
  • macrophage

Status

Published

Research group

  • Cardiovascular Research - Immunity and Atherosclerosis

ISBN/ISSN/Other

  • ISSN: 1537-1891