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Statins inhibit NK cell cytotoxicity by membrane raft depletion rather than inhibition of isoprenylation

  • Dianne Z. Hillyard
    Correspondence
    Corresponding author. Tel.: +44 141 330 5189; fax: +44 141 330 6972.
    Affiliations
    Renal Research Group, BHF Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom
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  • Cian D. Nutt
    Affiliations
    Renal Research Group, BHF Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom
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  • Jacqueline Thomson
    Affiliations
    Renal Research Group, BHF Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom
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  • Kenneth J. McDonald
    Affiliations
    Renal Research Group, BHF Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom
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  • Ray K. Wan
    Affiliations
    Renal Research Group, BHF Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom
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  • Angus J.M. Cameron
    Affiliations
    Renal Research Group, BHF Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom
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  • Patrick B. Mark
    Affiliations
    Renal Research Group, BHF Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom
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  • Author Footnotes
    1 Tel.: +44 141 330 2705; fax: +44 141 330 6972.
    Alan G. Jardine
    Footnotes
    1 Tel.: +44 141 330 2705; fax: +44 141 330 6972.
    Affiliations
    Renal Research Group, BHF Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom
    Search for articles by this author
  • Author Footnotes
    1 Tel.: +44 141 330 2705; fax: +44 141 330 6972.

      Abstract

      To investigate the potential determinants of the pleiotropic effects of statins, we measured NK cell cytotoxicity in samples from normal subjects and patients, including patients receiving statin therapy. In a multivariate analysis, NK cell cytotoxicity was related to total plasma cholesterol concentration rather than statin use. In vitro, we investigated the role of lipid modification, specifically the effects on membrane rafts and raft-dependent signal transduction. We demonstrate that statins reduce NK cell cytotoxicity and that membrane cholesterol depletion by cyclodextrins has a similar effect. In contrast, isoprenyl transferase inhibitors had little or no effect on NK cell function. We hypothesise that the pleiotropic effects of statins reflect changes in membrane cholesterol and, specifically, the density of membrane rafts. Moreover, there is likely to be a relationship between membrane cholesterol, membrane rafts and cell function that may be involved in the pathogenesis of cardiovascular and metabolic diseases.

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