Rosuvastatin reduces interleukin-6-induced expression of C-reactive protein in human hepatocytes in a STAT3- and C/EBP-dependent fashion.
OBJECTIVE
It has been speculated that the reduction in vascular events by statins may not only be due to lowering of cholesterol, but also to the decrease in plasma C-reactive protein (CRP). In the present study we investigated the possibility that rosuvastatin directly affected CRP expression in stimulated human hepatocytes.


METHODS
Interleukin 6 (IL-6) stimulated human hepatoma cells (Hep3B) and primary human hepatocytes (PHH) were incubated with various concentrations of rosuvastatin (0.3 - 1 microM) for 24 hours. CRP expression was determined using ELISA and quantitative real-time RT-PCR. The activation of STAT3 and C/EBP was investigated utilizing transcription factor assays (TransAM).


RESULTS
IL-6 increased CRP secretion by up to 5-fold in Hep3B and 6.6-fold in PHH. Rosuvastatin reduced CRP expression by 32% and 46% in Hep3B and PHH, respectively. IL-6 increased CRP mRNA up to 32-fold. At 1 microM, rosuvastatin reduced CRP mRNA by 73% compared to IL-6-stimulated cells. IL-6 activated the transcription factors STAT3 and C/EBP up to 2.6-fold and 2.2-fold, respectively. Rosuvastatin (1 microM) attenuated the activation of STAT3 and C/EBP by 48% and 54%, respectively.


CONCLUSIONS
Our results show a direct inhibitory effect of rosuvastatin on IL-6-induced expression of CRP in liver cells. Statins may lower CRP by inhibiting its production in the liver rather than by exerting systemic anti-inflammatory effects. The effects of rosuvastatin in reducing the levels of CRP in plasma may have clinical utility in addition to its effects on atherogenic lipoproteins.
Mayer
C
C
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Austria. claudia.mayer@klinikum-graz.at
Gruber
H J
HJ
Landl
E M
EM
Pailer
S
S
Scharnagl
H
H
Truschnig-Wilders
M
M
März
W
W
D000069059:Atorvastatin; D002097:C-Reactive Protein / Q000096:biosynthesis*; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D002478:Cells, Cultured; D005464:Fluorobenzenes / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007118:Immunoassay; D015850:Interleukin-6 / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000068718:Rosuvastatin Calcium; D050796:STAT3 Transcription Factor / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology*; D014157:Transcription Factors; D000093242:Interleukin-6 Inhibitors
D000069059:Atorvastatin; D002097:C-Reactive Protein; D022762:CCAAT-Enhancer-Binding Proteins; D005464:Fluorobenzenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D008798:Mevalonic Acid; D011743:Pyrimidines; D011758:Pyrroles; D012333:RNA, Messenger; D000068718:Rosuvastatin Calcium; D050796:STAT3 Transcription Factor; D013449:Sulfonamides; D014157:Transcription Factors; D000093242:Interleukin-6 Inhibitors