Statins as immunomodulators.
HMG-CoA reductase inhibitors, or statins, are effective lipid lowering agents, extensively used in medical practice. Statins have never been shown to be involved in the immune response, although few clinical reports have suggested a better outcome of cardiac transplantation in patients under pravastatin therapy. Major histocompatibility complex class II (MHC-II) molecules are directly involved in the activation of T lymphocytes and in the control of the immune response. Whereas only a limited number of specialized cell types express MHC-II constitutively, numerous other cells become MHC-II positive upon induction by interferon gamma (IFN-gamma). We and others recently demonstrated that statins act as direct inhibitors of induction of MHC-II expression by IFN-gamma and thus as repressors of MHC-II-mediated T cell activation. This effect was observed in several cell types, including primary human endothelial cells and macrophages. Interestingly, this inhibition is specific for inducible MHC-II expression and does not concern either constitutive expression of MHC-II or expression of MHC-I. In repressing induction of MHC-II, and subsequent T lymphocyte activation, statins therefore behave as a novel type of immunomodulator. This unexpected effect provides a scientific rationale for suggesting the use of statins as novel immunosuppressors, not only in organ transplantation but in numerous other pathologies as well.
Mach
François
F
Department of Medicine, University Hospital Geneva, Foundation for Medical Research, Switzerland. machf@cmu.unige.ch
D000818:Animals; D016027:Heart Transplantation; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D009687:Nuclear Proteins; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology
D000949:Histocompatibility Antigens Class II; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D007371:Interferon-gamma