Statins affect cell-surface expression of major histocompatibility complex class II molecules by disrupting cholesterol-containing microdomains.
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.
Division of Molecular Biology, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Hedwich F
HF
Kuipers
Paula J
PJ
Biesta
Tom A
TA
Groothuis
Jacques J
JJ
Neefjes
A Mieke
AM
Mommaas
Peter J
PJ
van den Elsen
D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D022162:Cytoplasmic Vesicles / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D021962:Membrane Microdomains / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology; D014176:Protein Biosynthesis / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects / Q000276:immunology; D019821:Simvastatin / Q000494:pharmacology; D020298:U937 Cells
D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D019821:Simvastatin