Statins differ in their ability to block NF-kappaB activation in human blood monocytes.
OBJECTIVE
The benefits of statin therapy in cardiovascular medicine are ascribed to its lipid-lowering effect as well as its anti-inflammatory properties. Whereas all statins have been shown to reduce cholesterol plasma levels, their effect on inflammatory markers has been inconsistent. Here, we show that statins differ markedly in their effectiveness in preventing activation of NF-kappaB, a transcription factor involved in the activation of immediately early genes during inflammation.


METHODS
Six statins (atorvastatin (Atv), cerivastatin (Cer), fluvastatin (Flu), lovastatin (Lov), pravastatin (Pra), simvastatin (Sim)) were tested for their ability to influence the induction of NF-kappaB in human monocytes (Mo) during inflammation. Mo isolated from healthy blood donors were incubated with LPS (10 microg/ml) in the presence and absence of statin (0.001-5 microM). NF-kappaB binding activity (EMSA), degradation and phosphorylation of the inhibitor protein IkappaB-alpha (Western blotting), tissue factor (TF) mRNA (rtPCR), and TF activity (clotting assay) were analyzed.


RESULTS
All statins inhibited LPS-induced NF-kappaB binding activity in Mo in a dose-dependent manner. The inhibitory effect was due to reduced phosphorylation and degradation of the NF-kappaB inhibitor protein IkappaB, and was primarily dependent on the absence of mevalonate. Whilst this effect appeared with all statins, there were marked differences in the degree of inhibition between the statins. Cer (45 +/- 9% inhibition, p < 0.05) was 9-fold more effective in reducing NF-kappaB activation than Flu (5 +/- 10% inhibition). The differences in the potency of statins (Cer > Atv > Sim > Pra > Lov > Flu) were also reflected at the transcriptional level and the protein level of NF-kappaB controlled tissue factor expression.


CONCLUSIONS
The finding that statins differ in their potency in interfering with the activation of NF-kappaB signaling in human monocytes further supports the hypothesis that some statins inhibit the inflammatory response more than others.
D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D000072000:NF-KappaB Inhibitor alpha; D013925:Thromboplastin