Ghittoni Raffaella, Napolitani Giorgio, Benati Daniela, Ulivieri Cristina, Patrussi Laura, Laghi Pasini Franco, Lanzavecchia Antonio, Baldari Cosima T
Department of Evolutionary Biology, University of Siena, Siena, Italy.
Eur J Immunol. 2006 Nov;36(11):2885-93. doi: 10.1002/eji.200636567.
Statins are widely used hypocholesterolemic drugs that inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, a rate-limiting enzyme of the mevalonate pathway whose biosynthetic endproduct is cholesterol. As a result of this activity, statins may perturb the composition of cell membranes, resulting in lipid raft disruption. Furthermore, by inhibiting protein prenylation, a process also dependent on mevalonate, statins block membrane targeting and activity of small GTPases. Antigen uptake, processing and presentation involve the interplay of Rab and Rho family GTPases. Furthermore, lipid rafts have been implicated both in antigen internalization by the BCR and in MHC class II clustering at the immunological synapse. Here we have addressed the effects of simvastatin on antigen processing and presentation by human B cells and dendritic cells. The results show that simvastatin potently suppresses tetanus toxoid processing and presentation to CD4+ T cells by HLA-DR by inhibiting protein antigen uptake through both receptor-mediated endocytosis and macropinocytosis. This effect can be largely accounted for by defective prenylation of Rho and Rab GTPases in the absence of any measurable perturbation of lipid rafts. In addition, simvastatin was found to preferentially affect the invariant chain-dependent MHC class II pathway, thereby identifying this route of antigen processing and presentation as a selective target of statins.
他汀类药物是广泛使用的降胆固醇药物，可抑制3-羟基-3-甲基戊二酰辅酶A还原酶，该酶是甲羟戊酸途径的限速酶，其生物合成终产物为胆固醇。由于这种作用，他汀类药物可能会扰乱细胞膜的组成，导致脂筏破坏。此外，通过抑制同样依赖甲羟戊酸的蛋白质异戊二烯化过程，他汀类药物会阻断小GTP酶的膜靶向和活性。抗原摄取、加工和呈递涉及Rab和Rho家族GTP酶的相互作用。此外，脂筏与BCR介导的抗原内化以及免疫突触处的MHC II类聚集均有关联。在此，我们研究了辛伐他汀对人B细胞和树突状细胞抗原加工和呈递的影响。结果表明，辛伐他汀通过抑制受体介导的内吞作用和巨吞饮作用摄取蛋白质抗原，从而强烈抑制破伤风类毒素的加工以及通过HLA-DR呈递给CD4+ T细胞。在脂筏未发生任何可测量扰动的情况下，Rho和Rab GTP酶的异戊二烯化缺陷在很大程度上可解释这种效应。此外，发现辛伐他汀优先影响恒定链依赖性MHC II类途径，从而将这种抗原加工和呈递途径确定为他汀类药物的选择性靶点。
