Simvastatin stimulates macrophage interleukin-1beta secretion through an isoprenylation-dependent mechanism.
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.
Lindholm
Marie W
MW
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
Nilsson
Jan
J
D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001549:Benzamides; D004791:Enzyme Inhibitors; C102520:GGTI 297; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053583:Interleukin-1beta; D016209:Interleukin-8; D008077:Lipoproteins, LDL; D014409:Tumor Necrosis Factor-alpha; D019821:Simvastatin; D051231:Farnesyltranstransferase