Statins as a newly recognized type of immunomodulator

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, or statins, are effective lipid-lowering agents, extensively used in medical practice(1-3). Statins have never been shown to be involved in the immune r esponse, although a report has indicated a better outcome of cardiac transp lantation in patients under Pravastatin therapy(4). Major histocompatibilit y complex class II (MHC-II) molecules are directly involved in the activati on 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 ga mma (IFN-gamma)(5). This complex regulation is under the control of the tra nsactivator CIITA (refs 6,7). Here we show that statins act as direct inhib itors of induction of MHC-II expression by IFN-gamma and thus as repressors of MHC-II-mediated T-cell activation. This effect of statins is due to inh ibition of the inducible promoter IV of the transactivator CIITA and is obs erved in several cell types, including primary human endothelial cells (ECs ) and monocyte-macrophages (M phi). It is of note that this inhibition is s pecific for inducible MHC-II expression and does not concern constitutive e xpression of CIITA and MHC-II. In repressing induction of MHC-II, and subse quent T-lymphocyte activation, statins therefore provide a new type of immu nomodulation. This unexpected effect provides a scientific rationale for us ing statins as immunosuppressors, not only in organ transplantation but in numerous other pathologies as well.