Chakrabarti R, Engleman E G
Department of Pathology, Stanford University School of Medicine, California 94305.
J Biol Chem. 1991 Jul 5;266(19):12216-22.
Upon stimulation with antigen or antibodies directed at the CD3.T cell receptor complex, T lymphocytes undergo a series of biochemical events that result in DNA synthesis and cellular proliferation. The purpose of the current study was to explore the role of mevalonic acid and its metabolites in this process. Stimulation of freshly isolated human T cells with immobilized anti-CD3 monoclonal antibody (mAb) results in the induction of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase message, with maximum induction occurring at 24 h of culture, approximately 12 h before the onset of DNA synthesis. Protein kinase C (PKC) probably mediates this induction, as H7, which inhibits PKC and cyclic nucleotide-dependent protein kinases, but not HA1004, which inhibits all of these protein kinases except PKC, completely abrogates the appearance of HMG-CoA reductase message. The importance of HMG-CoA reductase induction and mevalonate production in cell cycle progression was demonstrated by the observation that either 25-hydroxycholesterol, which inhibits this induction, or lovastatin, a competitive inhibitor of HMG-CoA reductase, inhibited anti-CD3-induced T cell mitogenesis in a dose-dependent manner. The presence of lovastatin during the first 24-36 h of culture results in a progressive delay of cell cycle progression, whereas this agent, when present only for the first 12 h of culture, had no effect on T cell proliferation. These results suggest that mevalonate is required for cell cycle progression from mid-G1 into late G1. Exogenous mevalonate overcomes the antiproliferative effect of lovastatin but not of 25-hydroxycholesterol. Since 25-hydroxycholesterol suppresses the metabolism of mevalonic acid at multiple points, this result suggests that one or more metabolites of mevalonate, rather than mevalonate itself, plays an essential role in cell cycle progression. One metabolite of mevalonate, farnesol pyrophosphate, may play such a role, since free farnesol suppresses anti-CD3 mAb-induced T cell proliferation in a concentration-dependent manner. In mAb is associated with PKC-dependent induction of HMG-CoA reductase which, in turn, leads to the generation of mevalonic acid and its metabolites, one or more of which play a requisite role in cell cycle progression.
在用抗原或针对CD3-T细胞受体复合物的抗体刺激后，T淋巴细胞会经历一系列生化事件，导致DNA合成和细胞增殖。本研究的目的是探讨甲羟戊酸及其代谢产物在此过程中的作用。用固定化抗CD3单克隆抗体（mAb）刺激新鲜分离的人T细胞会诱导3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶信息的产生，在培养24小时时诱导作用达到最大值，大约在DNA合成开始前12小时。蛋白激酶C（PKC）可能介导这种诱导作用，因为抑制PKC和环核苷酸依赖性蛋白激酶的H7能完全消除HMG-CoA还原酶信息的出现，而抑制除PKC外所有这些蛋白激酶的HA1004则不能。通过观察发现，抑制这种诱导作用的25-羟基胆固醇或HMG-CoA还原酶的竞争性抑制剂洛伐他汀均以剂量依赖性方式抑制抗CD3诱导的T细胞有丝分裂，这证明了HMG-CoA还原酶的诱导和甲羟戊酸的产生在细胞周期进程中的重要性。在培养的最初24至36小时内存在洛伐他汀会导致细胞周期进程逐渐延迟，而该药物仅在培养的最初12小时存在时，对T细胞增殖没有影响。这些结果表明，甲羟戊酸是细胞周期从中期G1期进入晚期G1期所必需的。外源性甲羟戊酸可克服洛伐他汀的抗增殖作用，但不能克服25-羟基胆固醇的抗增殖作用。由于25-羟基胆固醇在多个点抑制甲羟戊酸的代谢，这一结果表明甲羟戊酸的一种或多种代谢产物而非甲羟戊酸本身在细胞周期进程中起重要作用。甲羟戊酸的一种代谢产物法呢醇焦磷酸可能起这样的作用，因为游离法呢醇以浓度依赖性方式抑制抗CD3 mAb诱导的T细胞增殖。抗CD3 mAb与PKC依赖性诱导HMG-CoA还原酶有关，这反过来又导致甲羟戊酸及其代谢产物的产生，其中一种或多种在细胞周期进程中起必要作用。
