3-hydroxy-3-methylglutaryl coenzyme A reductase-independent inhibition of CD40 expression by atorvastatin in human endothelial cells.
OBJECTIVE
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert potent anti-inflammatory effects that are independent of their cholesterol-lowering action. We have investigated the effects of these drugs on cytokine-stimulated CD40 expression in human cultured endothelial cells and monocytes.


RESULTS
Reverse transcription-polymerase chain reaction and Western blot analysis revealed that treatment of either cell type with atorvastatin, cerivastatin, or pravastatin (1 to 10 micromol/L) inhibited interferon-gamma plus tumor necrosis factor-alpha-stimulated CD40 expression by approximately 50%, an effect that was not reversed by the HMG-CoA reductase product mevalonic acid (400 micromol/L). In contrast, mevalonic acid prevented the inhibitory effect of atorvastatin on cytokine-stimulated vascular cell adhesion molecule-1 expression and subsequent adhesion of THP-1 monocytes to the cultured endothelial cells. Transcription factor analysis revealed an inhibition by atorvastatin of nuclear factor-kappaB plus signal transducer and activator of transcription-1-dependent de novo synthesis of interferon regulatory factor-1, governing cytokine-stimulated CD40 expression in these cells. One consequence of this statin-dependent downregulation of CD40 expression was a decrease in CD40 ligand-induced endothelial interleukin-12 expression.


CONCLUSIONS
By interfering with cytokine-stimulated CD40 expression in vascular cells, statins thus seem capable of attenuating CD40 ligand-induced proinflammatory responses, including atherosclerosis. In addition, they point to the coexistence of HMG-CoA reductase-dependent and -independent effects of statins in the same cell type.
Wagner
Andreas H
AH
Department of Cardiovascular Physiology, University of Goettingen, Goettingen, Germany.
Gebauer
Matthias
M
Güldenzoph
Björn
B
Hecker
Markus
M
D000069059:Atorvastatin; D019013:CD40 Antigens / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D023201:CD40 Ligand / Q000378:metabolism / Q000502:physiology; D002450:Cell Communication / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D006538:Heptanoic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism / Q000502:physiology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018664:Interleukin-12 / Q000096:biosynthesis; D053762:Interleukin-12 Subunit p40; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008798:Mevalonic Acid / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D021122:Protein Subunits / Q000096:biosynthesis; D011758:Pyrroles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins / Q000166:cytology / Q000201:enzymology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D019013:CD40 Antigens; D016207:Cytokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D011758:Pyrroles; D019010:Vascular Cell Adhesion Molecule-1; D023201:CD40 Ligand; D018664:Interleukin-12; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid