Flescher E, Ledbetter J A, Schieven G L, Vela-Roch N, Fossum D, Dang H, Ogawa N, Talal N
Clinical Immunology Section, Audie L. Murphy Memorial Veterans Hospital, San Antonio, TX.
J Immunol. 1994 Dec 1;153(11):4880-9.
Products of polyamine oxidase activity, at micromolar levels and during a period of 2 to 3 days, down-regulate IL-2 mRNA levels and activity in human lymphocytes. We studied whether this suppression was associated with signal transduction abnormalities. We found that polyamine oxidase activity suppresses both anti-CD3-induced IL-2 production and protein tyrosine phosphorylation. Polyamine oxidase activity also caused a reduction in intracellular calcium mobilization after mitogenic stimulation. The most distal step of CD3-mediated signal transduction is dependent upon transcription factors that regulate a set of genes, including IL-2. We found that polyamine oxidase-treated cells exhibited very low DNA binding activity of two such factors: NFAT and NF-kappa B. On the other hand, AP-1 DNA binding activity was enhanced in polyamine oxidase-treated cells, suggesting a possible role for AP-1 in the human lymphocyte stress response. In accordance with the oxidation dependence of this suppressive mechanism, N-acetylcysteine (NAC; an antioxidant) significantly reversed the polyamine oxidase effects on lymphokine production and signal transduction. These results suggest that NAC contributes, under oxidizing conditions, to the preservation of immune function. In summary, our data suggest that chronic low-level oxidative stress, via suppression of mitogen-induced transmembrane signaling (protein-tyrosine phosphorylation and calcium mobilization), causes a decrease in the DNA binding activity of transcription factors that regulate the IL-2 gene. This results in decreased IL-2 production.
多胺氧化酶活性产物在微摩尔水平且在2至3天的时间段内，会下调人淋巴细胞中白细胞介素-2（IL-2）的mRNA水平和活性。我们研究了这种抑制作用是否与信号转导异常有关。我们发现多胺氧化酶活性既抑制抗CD3诱导的IL-2产生，也抑制蛋白酪氨酸磷酸化。多胺氧化酶活性还会导致有丝分裂原刺激后细胞内钙动员减少。CD3介导的信号转导的最远端步骤依赖于调节一组基因（包括IL-2）的转录因子。我们发现经多胺氧化酶处理的细胞中，两种此类因子：活化T细胞核因子（NFAT）和核因子κB（NF-κB）的DNA结合活性非常低。另一方面，在经多胺氧化酶处理的细胞中，活化蛋白-1（AP-1）的DNA结合活性增强，这表明AP-1在人淋巴细胞应激反应中可能发挥作用。根据这种抑制机制对氧化的依赖性，N-乙酰半胱氨酸（NAC；一种抗氧化剂）显著逆转了多胺氧化酶对淋巴因子产生和信号转导的影响。这些结果表明，在氧化条件下，NAC有助于维持免疫功能。总之，我们的数据表明，慢性低水平氧化应激通过抑制有丝分裂原诱导的跨膜信号转导（蛋白酪氨酸磷酸化和钙动员），导致调节IL-2基因的转录因子的DNA结合活性降低。这导致IL-2产生减少。
