Batuman O A, Ferrero A P, Diaz A, Berger B, Pomerantz R J
Hematology Division, SUNY Health Science Center at Brooklyn 11203.
Immunopharmacology. 1994 Jan-Feb;27(1):43-55. doi: 10.1016/0162-3109(94)90006-x.
To determine the mechanism of glucocorticoid (GC)-mediated inhibition of T cell functions, the effect of dexamethasone (DM) on T cell proliferation and interleukin-2 receptor (IL-2R) generation were studied. Dexamethasone inhibited IL-2-induced T cell proliferation by 30%-88%, relative to its concentration within the cultures. The effect of DM on expression of IL-2R alpha (Tac, p55, CD25) and beta (p75) genes in activated T cells was examined next. In T cells stimulated with purified phytohemagglutinin (PHA-p) and 4 beta-phorbol 12-myristate 13-acetate (PMA) addition of DM to the cultures resulted in a 60% reduction in IL-2R alpha and a 30% reduction in IL-2R beta membrane expression compared to T cells cultured in the absence of DM (p < 0.01). Inhibition of membrane IL-2R alpha and IL-2R beta expression by 10(-6) M DM was partially reversible by recombinant human IL-2 (rhIL-2). By Northern blot analysis, DM caused a comparable decrease in IL-2R alpha and in IL-2R beta mRNA levels to membrane receptor expression in mitogen-stimulated T cells. By in vitro transcription assays, DM regulated IL-2R alpha gene expression at a transcriptional level while transcription of IL-2R beta gene was unaffected by DM. The mechanism of action of DM on IL-2R alpha transcription was examined by determining the mRNA levels of the p50 subunit of nuclear factor kappa B (NF-kappa B), a transcription factor that stimulates IL-2R alpha gene expression. The data indicate that 10(-6) M DM increased T cell p50 NF-kappa B mRNA levels by four-fold compared to the levels obtained in the absence of DM. Further, the level of nuclear proteins capable of binding to the NF-kappa B sites in activated T cells increased in response to DM. In sum, DM regulates T cell membrane expression of IL-2R by more than one molecular mechanism.
为确定糖皮质激素（GC）介导的T细胞功能抑制机制，研究了地塞米松（DM）对T细胞增殖和白细胞介素-2受体（IL-2R）生成的影响。相对于培养物中的浓度，地塞米松抑制IL-2诱导的T细胞增殖30%-88%。接下来检测了DM对活化T细胞中IL-2Rα（Tac、p55、CD25）和β（p75）基因表达的影响。在用纯化的植物血凝素（PHA-p）和4β-佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）刺激的T细胞中，与未添加DM培养的T细胞相比，向培养物中添加DM导致IL-2Rα膜表达降低60%，IL-2Rβ膜表达降低30%（p<0.01）。10⁻⁶M DM对膜IL-2Rα和IL-2Rβ表达的抑制作用可被重组人IL-2（rhIL-2）部分逆转。通过Northern印迹分析，DM使丝裂原刺激的T细胞中IL-2Rα和IL-2Rβ mRNA水平降低程度与膜受体表达相当。通过体外转录试验，DM在转录水平调节IL-2Rα基因表达，而IL-2Rβ基因转录不受DM影响。通过测定核因子κB（NF-κB）p50亚基的mRNA水平来研究DM对IL-2Rα转录的作用机制，NF-κB是一种刺激IL-2Rα基因表达的转录因子。数据表明，与未添加DM时相比，10⁻⁶M DM使T细胞p50 NF-κB mRNA水平增加了四倍。此外，活化T细胞中能够与NF-κB位点结合的核蛋白水平因DM而增加。总之，DM通过多种分子机制调节T细胞膜IL-2R的表达。
