Statins Induce Regulatory T Cell Recruitment via a CCL1 Dependent Pathway1

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 immu-nomodulatory 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. The Journal of Immunology, 2008, 181: 3524–3534. T he statins are used extensively in medical practice be-cause of their ability to reduce cardiovascular mortalityand stroke (1). Although this protective activity was ini-tially ascribed to inhibition of cholesterol biosynthesis, it is now evident that statins are pleiotropic drugs with immunomodulatory and anti-inflammatory properties. Studies in animal models, a