Statins as a newly recognized type of immunomodulator

Abstract

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, 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 a report has indicated 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). This complex regulation is under the control of the transactivator CIITA (refs 6,7). Here we show 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 of statins is due to inhibition of the inducible promoter IV of the transactivator CIITA and is observed in several cell types, including primary human endothelial cells (ECs) and monocyte-macrophages (Mstraight phi). It is of note that 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 provide a new type of immunomodulation. This unexpected effect provides a scientific rationale for using statins as immunosuppressors, not only in organ transplantation but in numerous other pathologies as well.

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

“…These processes all involve changes in the actin cytoskeleton, which are controlled by small GTPases. Indeed, the inhibitory effect of statins on MHC II expression is reversed by mevalonate and GGPP but not squalene (Figure 1), suggesting the involvement of small GTPases as the underlying mechanism [92]. Similarly, Cdc42 and Rac regulate the ability of dendritic cells to present antigen to T cells [93].…”

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

“…Statins decrease T cell activation. In vitro, statins inhibit IFN␥-inducible class II major histocompatibility complex (MHC) expression in macrophages and ECs, an effect that is reversed by mevalonate (107). In contrast, statins have no effect on class I MHC expression in ECs.…”

“…In contrast, statins have no effect on class I MHC expression in ECs. Statins' inhibition of stimulated class II MHC expression is accompanied by decreased class II MHC mRNA levels and lower levels of class II MHC transactivator mRNA (107). Decreased expression of class II MHC proteins may lead to reduced T cell activation during antigen presentation: in mixed lymphocyte reactions, atorvastatin decreases T cell activation and proliferation (107).…”

“…Statins' inhibition of stimulated class II MHC expression is accompanied by decreased class II MHC mRNA levels and lower levels of class II MHC transactivator mRNA (107). Decreased expression of class II MHC proteins may lead to reduced T cell activation during antigen presentation: in mixed lymphocyte reactions, atorvastatin decreases T cell activation and proliferation (107). In addition, simvastatin has been shown to inhibit T cell ERK activation through a Ras-dependent mechanism, and to decrease T cell p38 activation by a Rhodependent mechanism; the former effect was reversed by FPP, and the latter by GGPP (108).…”

Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model

“…Statins have also been shown to modify the function of ECs, smooth muscle cells, platelets, and monocytes/macrophages (22). Their effects include decreasing the expression of adhesion molecules in monocytes and leukocyte-endothelial interactions (23)(24)(25)(26), inhibiting platelet function (27), inhibiting tissue factor expression by mononuclear cells (28,29), down-regulating inflammatory cytokines in ECs (30), increasing fibrinolytic activity (31,32), and immunomodulation by decreasing the expression of class II major histocompatibility complex antigen (33).…”