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Statins Impair CD1d-Mediated Antigen Presentation through the Inhibition of Prenylation ¹

Masood A. Khan^*, Richard M. Gallo^*, Gourapura J. Renukaradhya^*, Wenjun Du, Jacquelyn Gervay-Hague and Randy R. Brutkiewicz^2,*

^* Department of Microbiology and Immunology, Indiana University School of Medicine, Walther Oncology Center, Indianapolis, IN 46202, and the Walther Cancer Institute, Indianapolis, IN 46208; and Department of Chemistry, University of California, Davis, CA 95616

Statins are widely used as cholesterol-lowering agents that also decrease inflammation and target enzymes essential for prenylation, an important process in the activation and intracellular transport of proteins vital for a wide variety of cellular functions. Here, we report that statins impair a critical component of the innate immune response, CD1d-mediated Ag presentation. The addition of specific intermediates in the isoprenylation pathway reversed this effect, whereas specific targeting of enzymes responsible for prenylation mimicked the inhibitory effects of statins on Ag presentation by CD1d as well as MHC class II molecules. This study demonstrates the importance of isoprenylation in the regulation of Ag presentation and suggests a mechanism by which statins reduce inflammatory responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health grants RO1 AI46455 and PO1 AI056097 (to R.R.B.), and by NSF CHE-0194682 from the National Science Foundation (to J.G.H.). G.J.R. and R.M.G. were supported by National Institutes of Health Training Grants T32DK007519 and T32HLO7910, respectively.

² Address correspondence and reprint requests to Dr. Randy R. Brutkiewicz, Department of Microbiology and Immunology, Indiana University School of Medicine, 950 W. Walnut Street, Building R2, Room 302, Indianapolis, IN 46202. E-mail address: rbrutkie{at}iupui.edu

³ Abbreviations used in this paper: HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; BMDC, bone marrow-derived dendritic cell; -GalCer, -galactosylceramide; β-MCD, β-methyl cyclodextrin; FPP, farnesyl pyrophosphate; FTI, farnesyl transferase inhibitor; GGPP, geranylgeranyl pyrophosphate; GGTI, geranylgeranyl transferase inhibitor; HEL, hen egg lysozyme; HSA, human serum albumin; LAMP-1, lysosome-associated membrane protein 1; siRNA, small interfering RNA; VV, vaccinia virus.

⁴ The online version of this article contains supplemental material.