Immunosuppressive effects of statins.
3-Hydroxy-3-methhylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are effective lipid lowering agents, extensively used in medical practice [Circulation 2000;101:207; J Am Med Assoc 2000;283:2935]. Statins have never been shown to be involved in the immune response, although reports have suggested a better outcome of cardiac transplantation in patients under pravastatin therapy [New Engl J Med 1995;333:621; Circulation 1997;96:1398]. Major histocompatibility complex class II (MHC class 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) [Annu Rev Immunol 1996;14:301]. This complex regulation is under the control of the transactivator CIITA [Science 1994;265:106]. Recently, we 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 [Nat Med 2000;6:1399; Swiss Med Wkly 2001;131:41]. This effect of statins is due to inhibition of the inducible promoter IV of the transactivator CIITA. Interestingly, this inhibition is specific for inducible MHC-II expression and does not concern constitutive expression of CIITA and MHC-II. 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
Medicine Department, Cardiology Division, Foundation for Medical Research, Geneva Medical School, University Hospital, 64 Avenue Roseraie, 1211 Geneva, Switzerland.
D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D000949:Histocompatibility Antigens Class II / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006949:Hyperlipidemias / Q000188:drug therapy; D007371:Interferon-gamma / Q000187:drug effects / Q000276:immunology; D008148:Lovastatin / Q000494:pharmacology / Q000627:therapeutic use; D017035:Pravastatin / Q000494:pharmacology / Q000627:therapeutic use; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000949:Histocompatibility Antigens Class II; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007371:Interferon-gamma; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin