Anastassiou E D, Paliogianni F, Balow J P, Yamada H, Boumpas D T
Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
J Immunol. 1992 May 1;148(9):2845-52.
cAMP is an intracellular second messenger that conveys inhibitory signals for T cell activation and clonal proliferation. cAMP also inhibits the production of IL-2 and IL-2R alpha-chain expression. To determine the mechanisms of this inhibition, human peripheral blood T lymphocytes were stimulated with anti-CD3 mAb, PHA, PMA, or ionomycin, alone or in combination. cAMP elevation by PGE2, cholera toxin, or the cell-permeable analogue 8-bromo-cAMP inhibited the tyrosine phosphorylation of a protein of 100 kDa. This inhibition was associated with decreased IL-2 production and IL-2R alpha expression at both the protein product and the mRNA levels. Nuclear run-off assays showed that the inhibitory effect of cAMP on IL-2 and IL-2R alpha gene expression is mediated at the transcriptional level. H-8, an inhibitor of protein kinase A, reversed the inhibitory effect of cAMP on nuclear transcription of the IL-2 gene, suggesting that this is mediated through activation of protein kinase A. Post-transcriptionally, cAMP elevation decreased the t1/2 of IL-2 mRNA by more than 50%. These data indicate that cAMP inhibits cell membrane, cytoplasmic, and nuclear events associated with T cell activation and highlight the complexities of its action of lymphocyte function.
环磷酸腺苷（cAMP）是一种细胞内第二信使，它传递抑制T细胞活化和克隆增殖的信号。cAMP还抑制白细胞介素-2（IL-2）的产生以及IL-2受体α链的表达。为了确定这种抑制作用的机制，单独或联合使用抗CD3单克隆抗体、植物血凝素（PHA）、佛波酯（PMA）或离子霉素刺激人外周血T淋巴细胞。前列腺素E2（PGE2）、霍乱毒素或细胞可渗透类似物8-溴环磷酸腺苷（8-bromo-cAMP）引起的cAMP升高抑制了一种100 kDa蛋白质的酪氨酸磷酸化。这种抑制作用与蛋白质产物和mRNA水平上IL-2产生减少以及IL-2受体α表达降低有关。核转录分析表明，cAMP对IL-2和IL-2受体α基因表达的抑制作用是在转录水平介导的。蛋白激酶A抑制剂H-8逆转了cAMP对IL-2基因核转录的抑制作用，表明这是通过蛋白激酶A的激活介导的。在转录后水平，cAMP升高使IL-2 mRNA的半衰期缩短了50%以上。这些数据表明，cAMP抑制与T细胞活化相关的细胞膜、细胞质和核事件，并突出了其对淋巴细胞功能作用的复杂性。
