Statins affect cell-surface expression of major histocompatibility complex class II molecules by disrupting cholesterol-containing microdomains

Hedwich F Kuipers; Paula J Biesta; Tom A Groothuis; Jacques J Neefjes; A Mieke Mommaas; Peter J van den Elsen

doi:10.1016/j.humimm.2005.04.004

Statins affect cell-surface expression of major histocompatibility complex class II molecules by disrupting cholesterol-containing microdomains

Hum Immunol. 2005 Jun;66(6):653-65. doi: 10.1016/j.humimm.2005.04.004.

Authors

Hedwich F Kuipers¹, Paula J Biesta, Tom A Groothuis, Jacques J Neefjes, A Mieke Mommaas, Peter J van den Elsen

Affiliation

¹ Division of Molecular Biology, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.

PMID: 15993711
DOI: 10.1016/j.humimm.2005.04.004

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
HeLa Cells
Histocompatibility Antigens Class I / biosynthesis
Histocompatibility Antigens Class I / genetics
Histocompatibility Antigens Class II / biosynthesis*
Histocompatibility Antigens Class II / genetics
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
Intracellular Fluid / drug effects
Intracellular Fluid / immunology
Intracellular Fluid / metabolism
Membrane Microdomains / drug effects*
Membrane Microdomains / immunology*
Membrane Microdomains / metabolism
Promoter Regions, Genetic / drug effects
Promoter Regions, Genetic / immunology
Protein Biosynthesis / drug effects
Protein Transport / drug effects
Protein Transport / immunology
Simvastatin / pharmacology
U937 Cells

Substances

Histocompatibility Antigens Class I
Histocompatibility Antigens Class II
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Cholesterol
Simvastatin