Fluvastatin inhibits raft dependent Fcgamma receptor signalling in human monocytes.
Statins inhibit HMG-CoA reductase and thus block cholesterol and isoprenoid biosynthesis. Since statins also have anti-inflammatory effects, we investigated the effect of fluvastatin on monocyte Fcgamma receptor function. Fluvastatin (0.5-20 microM) inhibited Fcgamma receptor signal transduction at the level of tyrosine kinase activation, in a time and dose dependent manner. Initiation of tyrosine phosphorylation is not thought to involve prenylated proteins; thus, we hypothesised that fluvastatin might disrupt cholesterol and sphingolipid membrane rafts to impair signalling. Consistent with this hypothesis, fluvastatin decreased (and mevalonate rescued) signalling molecules within membrane rafts in parallel with effects on tyrosine phosphorylation events. Raft integrity was unaffected by prenyl transferase inhibitors. In addition, Fcgamma receptor mediated immune complex trafficking, activation of MAP kinases (ERK and p38), and downstream inflammatory mediator release (MMP-1 and IL-6) were blocked by fluvastatin. Thus, HMG-CoA reductase inhibition alters immune receptor signalling by disrupting membrane rafts essential for the initiation of signal transduction. Inhibition of Fcgamma receptor function may limit development and progression of atherosclerosis by decreasing monocyte/macrophage inflammatory mediator release. Since many receptors utilise cholesterol rich rafts this mechanism may have broader significance given the pleiotropic effects of statins.
Hillyard
Dianne Z
DZ
Division of Cardiovascular & Medical Sciences, University of Glasgow, Western Infirmary, Dumbarton Road, Glasgow G12 8QQ, UK.
Jardine
Alan G
AG
McDonald
Kenneth J
KJ
Cameron
Angus J M
AJ
D000936:Antigen-Antibody Complex / Q000187:drug effects; D001161:Arteriosclerosis / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005434:Flow Cytometry; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D015850:Interleukin-6 / Q000032:analysis; D020781:Matrix Metalloproteinase 1 / Q000032:analysis; D021962:Membrane Microdomains / Q000187:drug effects*; D009000:Monocytes / Q000187:drug effects*; D010766:Phosphorylation; D017452:Receptors, IgG / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D014443:Tyrosine / Q000378:metabolism
D000936:Antigen-Antibody Complex; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D015850:Interleukin-6; D017452:Receptors, IgG; D014443:Tyrosine; D000077340:Fluvastatin; D020781:Matrix Metalloproteinase 1