Statins Affect Cell-Surface Expression of Major Histocompatibility Complex Class II Molecules by Disrupting Cholesterol-Containing Microdomains

• Published in: Human Immunology 2005-06, Vol.66 (6), p.653-665
• Main Authors: Kuipers, Hedwich F., Biesta, Paula J., Groothuis, Tom A., Neefjes, Jacques J., Mommaas, A. Mieke, van den Elsen, Peter J.
• Format: Article
• Language: English
• Subjects: antigen presentation/processing; Cell Line, Tumor; Cell Membrane - drug effects; Cell Membrane - immunology; Cell Membrane - metabolism; Cholesterol - metabolism; Cytoplasmic Vesicles - drug effects; Cytoplasmic Vesicles - immunology; Cytoplasmic Vesicles - metabolism; Cytoplasmic Vesicles - ultrastructure; Gene Expression - drug effects; gene regulation; HeLa Cells; Histocompatibility Antigens Class I - biosynthesis; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class II - biosynthesis; Histocompatibility Antigens Class II - genetics; human; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Intracellular Fluid - drug effects; Intracellular Fluid - immunology; Intracellular Fluid - metabolism; lipid mediators; Membrane Microdomains - drug effects; Membrane Microdomains - immunology; Membrane Microdomains - metabolism; MHC; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - immunology; Protein Biosynthesis - drug effects; Protein Transport - drug effects; Protein Transport - immunology; Simvastatin - pharmacology; U937 Cells
• ISSN: 0198-8859; 1879-1166; 1365-2567
• DOI: 10.1016/j.humimm.2005.04.004

Statins, the main therapy for hypercholesterolemia, are currently considered as possible immunomodulatory agents. Statins inhibit the production of proinflammatory cytokines and reduce the expression of several immunoregulatory molecules, including major histocompatibility complex class II (MHC-II) molecules. In this study, we investigated the mechanism by which simvastatin reduces the membrane expression of MHC-II molecules on several human cell types. We demonstrate that the reduction of MHC-II membrane expression by simvastatin correlates with disruption of cholesterol-containing microdomains, which transport and concentrate MHC-II molecules to the cell surface. In addition, we demonstrate that statins reduce cell-surface expression of other immunoregulatory molecules, which include MHC-I, CD3, CD4, CD8, CD28, CD40, CD80, CD86, and CD54. Our observations indicate that the downregulation of MHC-II at the cell surface contributes to the immunomodulatory properties of statins and is achieved through disruption of cholesterol-containing microdomains, which are involved in their intracellular transport.