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* Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas (CSIC), Madrid, Spain;
Genetrix, Madrid, Spain; and
Theodor Kocher Institute, University of Bern, Bern, Switzerland
The statins, a group of inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are reported to influence a variety of immune system activities through 3-hydroxy-3-methylglutaryl coenzyme A reductase-dependent and -independent mechanisms. How statin treatment regulates immune system function in vivo nonetheless remains to be fully defined. We analyzed the immunomodulatory effects of lovastatin in a Candida albicans-induced delayed-type hypersensitivity reaction in mice. In this model, lovastatin administration reduced the acute inflammatory response elicited by C. albicans challenge. This anti-inflammatory activity of lovastatin was associated with a shift from a Th1 to a Th2 immune response, as well as an increase in the percentage of regulatory T cells at the inflammation site and in the regional draining lymph node. The lovastatin-induced increase in regulatory T cells in the inflamed skin was dependent on expression of CCL1, a chemokine that is locally up-regulated by statin administration. The anti-inflammatory effect of lovastatin was abrogated in CCL1-deficient mice. These results suggest that local regulation of chemokine expression may be an important process in statin-induced modulation of the immune system.
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1 This work was supported in part by the Spanish Ministry of Education and Science (SAF2005-00241 and NAN2004-08805-C04/04 to S.M.; SAF2006-07609 to C.A.), Fundación para la Investigación y Prevención del SIDA en España (36550/06 to S.M.), La Marato TV3 Foundation (to S.M.), the Comunidad de Madrid (DIFHEMAT-CM S-SAL-0304-2006 to S.M. and C.A.), and the European Union FP6 (INNOCHEM, FP6 LSHB-CT-2005-518167 to S.M. and C.M.A.). The Department of Immunology and Oncology was founded and is supported by the Spanish National Research Council and by Pfizer.
2 Address correspondence and reprint requests to Dr. Santos Mañes, Department of Immunology and Oncology, Centro Nacional de Biotecnología/Spanish National Research Council, Darwin 3, Madrid E-28049 Spain. E-mail address: smanes{at}cnb.csic.es
3 Abbreviations used in this paper: DTH, delayed-type hypersensitivity; Ct, cycle threshold; DC, dendritic cell; PO-LN, popliteal lymph node; SLO, secondary lymphoid organs; Treg, regulatory T; WT, wild type.
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