International Immunology Advance Access originally published online on December 20, 2006
International Immunology 2007 19(2):163-173; doi:10.1093/intimm/dxl133
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Lipophilic statins suppress cytotoxicity by freshly isolated natural killer cells through modulation of granule exocytosis
Gene Transfer and Immunogenicity Branch, Division of Cellular and Gene Therapies (HFM-725), Center for Biologics Evaluation and Research, Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892, USA
1 Present address: Department of Thoracic Surgery and Respiratory Disease, Nagahama City Hospital, Nagahama City, Shiga 526-8580, Japan
Correspondence to: E. T. Bloom; E-mail: eda.bloom{at}fda.hhs.gov
NK cells, a component of the innate immune system, provide a first line of defense against viral infections and malignancies, interact with the adaptive immune system and have a role in rejection of allogeneic bone marrow transplants and solid allo- and xenotransplants. Immunoregulatory activity by the anti-hypercholesterolemia agents, 3-hydroxy-3-methyl-glutaryl Coenzyme A (HMG-CoA) reductase inhibitors, known as statins, has recently been reported. We analyzed the effects of three statins on human NK cell cytotoxicity. Two lipophilic statins (simvastatin and fluvastatin) suppressed the cytotoxic activity of fresh and IL-2-stimulated NK cells, while pravastatin, a hydrophilic statin, did not. Suppression was not associated with changes in intracellular perforin, granzyme A or granzyme B levels, or with changes in expression of leukocyte function-associated antigen-1, an integrin known to regulate NK activity and reported to be altered by statin treatment. Decreased cytotoxicity was associated with decreased CD107a surface expression, indicating that the exocytosis pathway was compromised by simvastatin and fluvastatin but not by pravastatin. Mevalonate, the immediate downstream product of HMG-CoA reductase, partially reversed the effect of lipophilic statins on cytotoxicity and CD107a expression. Lipophilic statins also suppressed the release of the granule component, granzyme B, by IL-2-activated NK cells following stimulation with K562. That lipophilic statins suppress NK cell activity through inhibition of the exocytosis pathway suggest an additional potential role for statins in inhibition of transplantation responses.
Keywords: CD107a, granzyme B, human, NK cells, statins
* These authors contributed equally to this study.
Transmitting editor: K. Okumura
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