曲古抑菌素A抑制小鼠CD4^＋T细胞活化的机制

Trichostatin A inhibits the activation of CD_4^+ T cells by suppressing CD_(28) expression in mice

目的研究组蛋白去乙酰化酶抑制剂曲古抑菌素A(TSA)对小鼠脾脏CD4+T细胞相关分子的基因转录和表达以及对活化信号转导途径的影响,探讨TSA影响CD4+T细胞活化的作用机制。方法采用2、20、200 nmol/L倍比浓度TSA作用于C57BL小鼠脾脏中分离出的CD4+T细胞24 h,观察对CD3,CD28以及IL-2基因转录和表达的影响;观察TSA对采用抗CD3,CD28单抗激活CD4+T细胞表达蛋白酶ZAP70和PI3K的影响。结果 TSA能抑制CD4+T细胞CD28基因转录和分子表达,且与作用浓度相关;能抑制抗体激活的小鼠CD4+T细胞表达PI3K蛋白,而对CD3分子活化信号下游的ZAP70蛋白的表达无明显影响;TSA还能抑制CD4+T细胞IL-2的基因转录和显著减少激活的CD4+T细胞表达IL-2(P<0.01)。结论 TSA通过抑制CD28基因转录和分子表达,影响激活CD4+T细胞活化过程中共刺激信号向细胞内的传导,减少IL-2的分泌,从而降低CD4+T细胞的免疫活性。

Objective To investigate the mechanism of trichostatin A（TSA）,a histone deacetylase（HDAC） inhibitor,in inhibiting the activation of CD4＋ T cells in mice.Methods The CD4＋ T cells isolated from the spleen of C57BL mice were treated with different concentrations of TSA（2,20,and 200 nmol/L） for 24 h,and CD3,CD28 and interleukin-2（IL-2） mRNA levels were measured with reverse transcription-polymerase chain reaction.The protein expressions of CD3,CD28 and IL-2 were measured by fluorescence-activated cell sorting and ELISA analysis.ZAP70 and PI3K protein expression in CD4＋ T cells activated by CD3 and CD28 monoclonal antibody were analyzed by Western blotting.Results TSA dose-dependently inhibited the transcription and protein expression of CD28 in CD4＋ T cells and reduced the expression of PI3K protein in activated CD4＋ T cells,without showing significant effect on the expression of ZAP70.TSA treatment of the cells also resulted in significantly decreased mRNA and protein expressions of IL-2（P0.01）.Conclusion TSA can regulate the immunological activity of CD4＋ T cells by inducing mRNA and protein expressions of CD28,which inhibits the activation of the co-stimulatory signal transduction in CD4＋ T cells and decreases the secretion of IL-2.