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Statins reduce interleukin-6-induced C-reactive protein in human hepatocytes: new evidence for direct antiinflammatory effects of statins.

Abstract

OBJECTIVE

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.

CONCLUSIONS

These results demonstrate that statins reduce IL-6-induced CRP production directly in hepatocytes via inhibition of protein geranylgeranylation. We further show that statins act via inhibition of STAT3 phosphorylation. These findings furnish new evidence for direct antiinflammatory properties of statins and provide new mechanistic insight into their clinical benefits.

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  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Division of Cardiology, Foundation for Medical Research, Faculty of Medicine, Geneva University Hospital, Switzerland.

    , , , , ,

    Source

    MeSH

    Anti-Inflammatory Agents
    Atorvastatin
    C-Reactive Protein
    Carcinoma, Hepatocellular
    Cell Line, Tumor
    Hepatocytes
    Heptanoic Acids
    Humans
    Hydroxymethylglutaryl-CoA Reductase Inhibitors
    Interleukin-6
    Liver Neoplasms
    Phosphorylation
    Pravastatin
    Protein Prenylation
    Pyrroles
    RNA, Messenger
    STAT3 Transcription Factor
    Simvastatin

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    15790934

    Citation

    TY - JOUR T1 - Statins reduce interleukin-6-induced C-reactive protein in human hepatocytes: new evidence for direct antiinflammatory effects of statins. AU - Arnaud,Claire, AU - Burger,Fabienne, AU - Steffens,Sabine, AU - Veillard,Niels R, AU - Nguyen,Tuan Huy, AU - Trono,Didier, AU - Mach,François, Y1 - 2005/03/24/ PY - 2005/3/26/pubmed PY - 2005/12/22/medline PY - 2005/3/26/entrez SP - 1231 EP - 6 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler. Thromb. Vasc. Biol. VL - 25 IS - 6 N2 - OBJECTIVE: 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. CONCLUSIONS: These results demonstrate that statins reduce IL-6-induced CRP production directly in hepatocytes via inhibition of protein geranylgeranylation. We further show that statins act via inhibition of STAT3 phosphorylation. These findings furnish new evidence for direct antiinflammatory properties of statins and provide new mechanistic insight into their clinical benefits. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/15790934/full_citation L2 - http://www.ahajournals.org/doi/full/10.1161/01.ATV.0000163840.63685.0c?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed ER -