Relevance of the mevalonate biosynthetic pathway in the regulation of bone marrow mesenchymal stromal cell-mediated effects on T-cell proliferation and B-cell survival
Relevance of the mevalonate biosynthetic pathway in the regulation of bone marrow mesenchymal stromal cell-mediated effects on T-cell proliferation and B-cell survival
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DOI：
10.3324/haematol.2010.031633
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发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Poggi, Alessandro
中科院分区：
文献类型：
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作者：
Musso, Alessandra;Zocchi, Maria Raffaella;Poggi, Alessandro
背景骨髓间充质干细胞可以抑制T淋巴细胞的增殖，但促进正常和恶性B细胞的存活，因此可能成为新的治疗方案的靶点。在此，我们定义了胆固醇合成抑制剂对这些间充质基质细胞与T或B淋巴细胞相互作用的影响。设计与方法我们将间充质基质细胞暴露于氟伐他汀等3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，该酶负责合成胆固醇的前体甲氧戊酸。此外，这些细胞还被甘露霉素A处理，这是一种酰胺基转移酶抑制剂，可以阻断甲氧戊酸依赖的小三磷酸鸟苷结合蛋白的异戊二烯基化。首先，对间充质基质细胞的形态、细胞骨架组装、细胞周期、存活率和细胞因子的产生进行了评价。结果氟伐他汀改变了肌动蛋白微丝的组装，灭活了RhoA鸟苷结合蛋白，抑制了细胞周期的S期，诱导了一小部分细胞的凋亡，但保留了细胞因子的产生。间充质干细胞与氟伐他汀或曼霉素A预育，可下调黏附分子的表达，减少细胞与细胞间的相互作用，并阻止这些基质细胞对CD3/T细胞受体诱导的淋巴细胞增殖的抑制。甲伐他汀可逆转氟伐他汀的形态、表型和功能效应。最后，在地塞米松存在的情况下，氟伐他汀显著减少了间充质基质细胞对B细胞的拯救，尽管它在没有corticosteroids.ConclusionsFluvastatin-mediated的情况下不起作用。可以想见，骨髓间充质基质细胞的作用可能是由于抑制了小的鸟苷三磷酸结合蛋白的异戊二烯基化，而缺乏甲氧戊酸的情况下发生的。总之，这些发现表明，作用于甲氧戊酸生物合成途径的药物可以调节间充质基质细胞诱导的T细胞抑制和B淋巴细胞存活。
BackgroundBone marrow mesenchymal stromal cells can suppress T-lymphocyte proliferation but promote survival of normal and malignant B cells, thus representing a possible target for new therapeutic schemes. Here we defined the effects of cholesterol synthesis inhibitors on the interaction between these mesenchymal stromal cells and T or B lymphocytes.Design and MethodsWe exposed mesenchymal stromal cells to inhibitors, such as fluvastatin, of the 3-hydroxy-3-methylglutaryl-coenzymeA reductase, responsible for the synthesis of mevalonate, the precursor of cholesterol. Also, these cells were treated with manumycin A, a famesyl transferase inhibitor which blocks the mevalonate-dependent isoprenylation of small guanosin triphosphate binding proteins. First, mesenchymal stromal cell morphology, cytoskeleton assembly, cell cycle, survival and cytokine production were evaluated. Then, these cells were co-cultured with either T or B lymphocytes and we analyzed: 1) the inhibition of T-cell proliferation to mitogenic stimuli; 2) B-cell survival.ResultsFluvastatin altered the assembly of actin microfilaments, inactivated RhoA guanosin triphosphate binding protein, inhibited the S-phase of the cell cycle, induced apoptosis in a small fraction of cells but preserved cytokine production. Preincubation of mesenchymal stromal cells with fluvastatin, or manumycin A, down-regulated the expression of adhesion molecules, reduced cell-to-cell interactions and prevented the inhibition exerted by these stromal cells on CD3/T-cell receptor-induced lymphocyte proliferation. Mevalonic acid could revert morphological, phenotypic and functional effects of fluvastatin. Finally, fluvastatin significantly reduced the mesenchymal stromal cells-mediated rescue of B cells in the presence of dexamethasone, although it did not function in the absence of corticosteroids.ConclusionsFluvastatin-mediated effects on bone marrow mesenchymal stromal cells were conceivably due to the inhibition of isoprenylation of small guanosin triphosphate binding proteins, occurring for the lack of mevalonate. Altogether these findings suggest that drugs acting on the mevalonate biosynthetic pathway can regulate mesenchymal stromal cell-induced T-cell suppression and B-lymphocyte survival.