Simvastatin impairs humoral and cell‐mediated immunity in mice by inhibiting lymphocyte homing, T‐cell activation and antigen cross‐presentation

Abstract

Statins block the activity of HMG-CoA reductase, which catalyses the production of mevalonate, an intermediate in cholesterol biosynthesis, which is also a precursor of isoprenoids. In addition to lowering circulating cholesterol, these drugs display antiinflammatory and immunomodulatory activities in vitro; however, their effects on the development of adaptive immune responses in vivo, as well as the underlying mechanisms, are as yet largely unknown. Here we investigated the outcome of simvastatin treatment on a number of processes, which together orchestrate adaptive immunity to specific antigen. Simvastatin treatment resulted in a marked reduction of T and B cells in spleen, lymph nodes and peripheral blood in mice. This effect could be ascribed principally to an impairment of lymphocyte homing to secondary lymphoid organs. In addition, simvastatin was found to strongly inhibit T-cell responses to the MHCI restricted hen ovalbumin peptide antigen SIINFEKL and to impair ovalbumin uptake and cross-presentation by MHCI. Simvastatin also suppressed antibody responses to immunization with ovalbumin and delayed-type hypersensitivity to allergens. These activities could be largely accounted for by the simvastatin-dependent inhibition of HMG-CoA reductase. The data provide novel mechanistic insight into the activities of simvastatin in the highly complex context of the immune response.Key words: Apoptosis . Homing . Immune responses . Simvastatin IntroductionStatins are competitive inhibitors of HMG-CoA reductase, a major rate-limiting enzyme that controls HMG-CoA conversion to mevalonic acid in the cholesterol biosynthetic pathway. In addition to lowering circulating cholesterol, statins act as antiinflammatory and immunomodulatory agents [1]. These activities have been largely ascribed to their capacity to block isoprenoid production, and thereby to inhibit prenylation of small Ras superfamily GTPases, which are master regulators of cell activation and proliferation, cytoskeletal remodelling and membrane trafficking [2].Statins suppress T-cell activation both directly and by interfering with APC maturation and function. Statins inhibit T-cell activation, cell cycle progression and proliferation, as well as migration, both through an HMG-CoA-reductase-independent mechanism, involving allosteric inhibition of LFA-1 [3] and HMGCoA-reductase-dependent mechanisms, which rely on their capacity to inhibit prenylation of small GTPases [4,5]. Moreover, recent reports have provided evidence that some statins also 2832affect helper T-cell differentiation by promoting Th2 polarization and suppressing Th1 polarization both in vitro and in vivo [6,7]. This activity highlights statins as potential drugs in the treatment of diseases dominated by Th1 responses. Statins have been indeed shown to prevent or reverse several Th1-mediated autoimmune conditions in mice, such as autoimmune encephalomyelitis [8], spontaneous systemic lupus erythematosus [9,10], autoimmune myocarditis [11] and autoimmune retinal disease [12] via suppressio...

Prevention of transplant coronary artery disease by prenylation inhibitors

“…Previous in vivo and in vitro studies have shown that modification of the innate and acquired immune responses by statins contributes to their anti-inflammatory properties via decreased adhesion molecule expression, antigen presentation, cytokine production, receptor signaling and T-cell activation and proliferation. 11,19,20 This study has confirmed that AT slows the development of TCAD, as well as allograft CD4 ϩ T cells and macrophage recruitment. Previous studies, by our group and others, have reported that CD4 ϩ T cells and macrophages play a pathogenic role in the development of TCAD in this model system.…”

Baccatin III, a synthetic precursor of taxol, enhances MHC-restricted antigen presentation in dendritic cells

“…On the other hand, it was previously reported that cyclosporin A and tacrolimus, which are the principal drugs used to suppress transplantation rejection, profoundly inhibit the class I and class II MHC-restricted presentation of antigenic peptides both in vitro and in vivo, suggesting that the immunosuppressive activity of cyclosporin A and tacrolimus is at least in part due to the inhibition of the antigen processing pathways [10][11][12]. Simvastatin, an inhibitor of HMG-CoA reductase which is a major rate-limiting enzyme in the cholesterol biosynthesis pathway, has also been reported to inhibit the class I MHC-restricted presentation of exogenous antigen [13]. Inhibition of MHC-restricted antigen presentation has also been reported on nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen [14].…”

Efeito da sinvastatina em dose imunossupressora sobre as glândulas salivares e linfonodos cervicais de ratos Wistar

“…O reconhecimento, ativação e expansão clonal pelos linfócitos é essencial para uma resposta imune adaptativa eficaz 32 . Sabe-se que a sinvastatina age sobre o sistema imunológico inato e adquirido, regulando a ativação de neutrófilos, macrófagos, da resposta imune celular (Th1), humoral (Th2), diminuindo a migração de células T e B para os órgãos linfóides secundários (baço, linfonodos) e de leucó-citos para o sangue periférico, e a apresentação de antígenos via MHC de classe I e II 6,[33][34][35][36][37] . A migração dos linfócitos para os locais de infecção e órgãos linfoides secundários é governada pela adesão de moléculas, uma delas é a LFA-1 (antíge-no 1 associado a função do linfócito), esta quando associada ao ligante ICAM-1 aumenta a adesão dos linfócitos a paredes dos vasos 6 .…”

“…Linfonodos cervicais fazem parte dos órgãos linfoides periféricos e participam da imunidade adaptativa, os antígenos são apresentados aos linfócitos pelas células apresentadoras de antígenos e proteínas do maior complexo de histocompatibilidade, iniciando assim a ativação de linfócitos e expansão clonal 6 . As estatinas são inibidores da 3-hidroxi -3-metilglutaril coenzima A reductase (HMG-CoA) uma enzima que catalisa a produção do melavonato, o colesterol é um dos produtos desta via e a interrupção da mesma leva a queda dos níveis lipídicos, além disso, apresenta propriedades anti-inflamatórias e imunomoduladoras 7 . Estudos têm mostrado que a sinvastatina pode ser usada como agente imunomodulador da ação inflamatória, com potenciais implicações terapêuticas no tratamento de doenças inflamatórias crônicas [8][9][10][11] .…”