Statins Reduce Interleukin-6–Induced C-Reactive Protein in Human Hepatocytes

Abstract

Objectives-Besides its predictive role in determining cardiovascular risk, C-reactive protein (CRP) may exert direct proatherogenic effects through proinflammatory properties. CRP is mainly produced by hepatocytes in response to interleukin-6 (IL-6) and is then released into the systemic circulation. 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors, or statins, significantly reduce cardiovascular events and mortality in patients with or without coronary artery disease and reduce plasma CRP levels in humans. However, the mechanism by which statins reduce plasma CRP levels remains unknown. Methods and Results-In this study, we report that statins limit both protein and RNA levels of IL-6-induced CRP in human hepatocytes. These effects are reversed by L-mevalonate and mimicked by an inhibitor of the geranylgeranyltransferase. IL-6 -induced CRP production requires the binding of IL-6 to its cognate receptors, which results in activation and phosphorylation of the transcription factor STAT3. We provide evidence that statins reduce this IL-6 -induced phosphorylation of STAT3 in hepatocytes. Recent clinical trials showed that C-reactive protein (CRP) is a powerful independent predictor of future cardiovascular events. 2,5 CRP, the major acute-phase reactant in humans, derives mainly from hepatocytes in response to interleukin-6 (IL-6) 6 and is then secreted into the systemic circulation. Recent studies reported that besides its predictive role in determining cardiovascular risk, CRP can exert a direct proatherogenic role. CRP can accelerate the progression of atherosclerosis in apolipoprotein E (apoE)-deficient mice. 7 In vitro studies reporting that CRP modulates the activity and expression of multiple factors implicated in atherogenesis provided further evidence for the proatherogenic role of CRP. CRP downregulates endothelial nitric oxide synthase, 8 resulting in decreased release of NO, and thus facilitates endothelial cell apoptosis and inhibition of angiogenesis. 9 In addition, CRP stimulates the production of the vasoconstrictor endothelin-1 and the inflammatory marker IL-6 by endothelial cells. 10 Furthermore, CRP increases the expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, 11 and monocyte chemoattractant protein-1 (MCP-1), resulting in enhanced leukocyte transmigration. 12 Recent data suggest that CRP itself potently chemoattracts monocytes 13 and facilitates the uptake of low-density lipoprotein (LDL) by macrophages. 14 In smooth muscle cells, CRP upregulates angiotensin type 1 receptor and stimulates smooth muscle cells migration and proliferation and reactive oxygen species production. 15 3-hydroxy-3-methylglutaryl-coenzymeA (HMG-CoA) reductase inhibitors, or statins, effectively lower serum cholesterol levels and significantly reduce cardiovascular events and mortality in patients with or without coronary artery disease. 16 Recently, statins have also been characterized by their immunomodulatory effects, [17][18][19] as well as antiinfl...

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Ezetimibe: cholesterol lowering and beyond

“…In single studies, statin-induced lowering of LDL-C and reductions in hsCRP correlate weakly [100], though a recent meta-analysis of LDL-C lowering intervention trials showed a strong correlation between LDL-C and hsCRP [101]. This suggests that different individuals may vary in achieving the amount of LDL-C lowering required to reduce inflammatory responses reflected by hsCRP [102].…”

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Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

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