Document Detail


Simvastatin stimulates macrophage interleukin-1beta secretion through an isoprenylation-dependent mechanism.
MedLine Citation:
PMID:  16942919     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Statin treatment inhibits oxidized lipoprotein-induced intracellular lipid accumulation (foam cell formation) and reduces plasma levels of inflammatory markers such as interleukin-1beta (IL-1beta). 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-1beta 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 IL-1beta and IL-8 secretion. Simvastatin-stimulated IL-1beta secretion from macrophages was inhibited by isoprenoids. We therefore hypothesized that simvastatin stimulated IL-1beta 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 GGTI-297 and FTInhI. This treatment resulted in strong stimulation of IL-1beta secretion that was further enhanced when exogenous IL-1beta was present at the beginning of treatment. These data suggest an isoprenylation-dependent negative-feedback loop for macrophage IL-1beta secretion that is inhibited by statin treatment.
Authors:
Marie W Lindholm; Jan Nilsson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-07-25
Journal Detail:
Title:  Vascular pharmacology     Volume:  46     ISSN:  1537-1891     ISO Abbreviation:  Vascul. Pharmacol.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2006-12-25     Completed Date:  2007-03-21     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  101130615     Medline TA:  Vascul Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  91-6     Citation Subset:  IM    
Affiliation:
Experimental Cardiovascular Research, Department of clinical science, Malmö, Faculty of Medicine, Lund University, CRC, UMAS Ing. 72, 20502 Malmö, Sweden. Marie.Lindholm@med.lu.se
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MeSH Terms
Descriptor/Qualifier:
Benzamides / pharmacology
Cells, Cultured
Enzyme Inhibitors / pharmacology
Farnesyltranstransferase / antagonists & inhibitors,  metabolism
Feedback, Physiological / drug effects
Foam Cells / drug effects,  metabolism
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
Interleukin-1beta / metabolism*,  pharmacology
Interleukin-8 / metabolism
Lipid Metabolism / drug effects*
Lipoproteins, LDL / metabolism
Macrophages / drug effects*,  metabolism
Protein Prenylation / drug effects*
Simvastatin / pharmacology*
Tumor Necrosis Factor-alpha / metabolism
Chemical
Reg. No./Substance:
0/Benzamides; 0/Enzyme Inhibitors; 0/GGTI 297; 0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/Interleukin-1beta; 0/Interleukin-8; 0/Lipoproteins, LDL; 0/Tumor Necrosis Factor-alpha; 79902-63-9/Simvastatin; EC 2.5.1.29/Farnesyltranstransferase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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