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Inhibition Of Proliferation And Signalling Mechanisms In Human Lymphocytes By Fluvastatin
Author(s) -
Hillyard Dianne Z,
Cameron Angus JM,
McIntyre Alan H,
Hadden Mark H,
Marshall Hilary E,
Johnston Nicola,
Jardine Alan G
Publication year - 2002
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1046/j.1440-1681.2002.03711.x
Subject(s) - fluvastatin , pharmacology , mevalonic acid , statin , hmg coa reductase , signal transduction , prenylation , mevalonate pathway , kinase , reductase , biology , chemistry , biochemistry , enzyme , simvastatin
SUMMARY 1. Inhibitors of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase (statins) reduce serum cholesterol and have proven benefits in the treatment of cardiovascular disease. However, recent work suggests that statins may exert immunosuppressive effects in isolated lymphocytes and in solid organ transplant recipients. Fluvastatin does not interfere with the metabolism of commonly used immunosuppressive agents and, therefore, may have benefits in transplant recipients. 2. The aim of the present study was to investigate the potential immunomodulatory effects of fluvastatin in vitro in human lymphocytes and the underlying effects on signal transduction. 3. In vitro , fluvastatin (10 μ mol/L) caused a time‐dependent inhibition of T cell proliferation in response to cross‐linking of CD3. 4. Thymidine incorporation was reduced by 22, 81 and 92% at days 1, 3 and 5, respectively. 5. Mevalonate (1 μ mol/L) treatment for 4 or 24 h significantly reduced the inhibitory effects of fluvastatin; the reversal was abrogated by simultaneous exposure to mevalonate and a farnesyl transferase inhibitor. 6. At a subcellular level, fluvastatin treatment was associated with reduced functional activity of Ras‐dependent extracellular signal‐regulated kinase pathways and of Rho‐dependent p38 activation. 7. These data suggest that the potential immunosuppressive actions of statins involve inhibition of subcellular pathways dependent on isoprenylation of signal peptides, including Ras, Rho and related G‐proteins.