Inhibition Of Proliferation And Signalling Mechanisms In Human Lymphocytes By Fluvastatin

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 sol...

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Published in:	Clinical and experimental pharmacology & physiology Vol. 29; no. 8; pp. 673 - 678
Main Authors:	Hillyard, Dianne Z, Cameron, Angus JM, McIntyre, Alan H, Hadden, Mark H, Marshall, Hilary E, Johnston, Nicola, Jardine, Alan G
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Science Pty 01-08-2002
Subjects:	3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor Cell Division - drug effects Cell Division - physiology farnesyl Fatty Acids, Monounsaturated - pharmacology Fluvastatin geranylgeranyl Growth Inhibitors - pharmacology Humans Immunosuppressive Agents - pharmacology Indoles - pharmacology MAP Kinase Signaling System - drug effects MAP Kinase Signaling System - physiology Mitogen-Activated Protein Kinases - antagonists & inhibitors Mitogen-Activated Protein Kinases - metabolism p38 Mitogen-Activated Protein Kinases Ras T-Lymphocytes - cytology T-Lymphocytes - drug effects T-Lymphocytes - enzymology
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Summary:	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 μmol/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 μmol/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.
Bibliography:	ark:/67375/WNG-BK72L716-B ArticleID:CEP3711 istex:1A63627CD5BE02273A908BA0CE94F0DDFFF3D393 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0305-1870 1440-1681
DOI:	10.1046/j.1440-1681.2002.03711.x