Medizinische Universität Graz - Research portal
Selected Publication:
Mayer, C.
Reduction of IL-6 induced CRP expression in human hepatocytes by the HMG-CoA reductase inhibitor Rosuvastatin.
[ Dissertation ] Graz Medical University; 2006.
- Authors Med Uni Graz:
- Bernecker Claudia
- Advisor:
- Obermayer-Pietsch Barbara
- Renner Wilfried
- Altmetrics:
- Abstract:
- It has been speculated that the reduction of vascular events by statins may not only be due to their cholesterol-lowering activities, but to the decrease of plasma C-reactive protein (CRP). In the present study we investigated the possibility that rosuvastatin directly affected CRP expression in stimulated human hepatocytes. In the present study, IL-6 stimulated human hepatoma cells (Hep3B) and primary human hepatocytes (PHH) were incubated for 24h with various concentrations of rosuvastatin and the release of CRP was determined by ELISA. IL-6 increased CRP up to 5.0-fold in Hep3B and 6.6-fold in PHH. Rosuvastatin (1M) reduced CRP expression by 32% and 46% in Hep3B and PHH, respectively. Co-incubation with L-mevalonate blunted the inhibitory effect of Rosuvastatin, showing specificity of interaction. IL-6 increased CRP mRNA, determined by combined reversed and amplifying real-time PCR, up to 32-fold. At 1M, rosuvastatin reduced CRP mRNA by 73% compared to IL-6 stimulated cells. Effects of rosuvastatin on transcription factors STAT3 and C/EBP were investigated by utilizing transcription factor binding assays. IL-6 activated STAT3 and C/EBP up to 2.6-fold and 2.2-fold, respectively. Rosuvastatin [1M] attenuated the activation of STAT 3 and C/EBP by 48% and 54%, respectively. Specific knock-downs of STAT3 and C/EBP p50 with corresponding decoyODNs resulted in a decrease of CRP mRNA by 72% and 51%, respectively. Our results show a direct inhibitory effect of rosuvastatin on IL-6 induced CRP expression in liver cells via STAT3 and C/EBP inhibition. These results further indicate that statins may lower CRP by inhibiting its expression in the liver rather than by exertin systemic anti-inflammatory effects. As CRP is postulated to have an active role in ahterogenesis, the effects of rosuvastatin in reducing the levels of CRP in plasma may have clinical utility in addition to its effects on the atherogenic lipoproteins.