De Krey G K, Kerkvliet N I
Department of Agricultural Chemistry, Oregon State University, Corvallis 97331, USA.
Toxicology. 1995 Mar 31;97(1-3):105-12. doi: 10.1016/0300-483x(94)02929-o.
Previous studies have shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent immunosuppressive compound. In our laboratory, TCDD and structurally related polychlorinated biphenyls (PCBs) have been shown to suppress alloantigen-specific cytotoxic T lymphocyte (CTL) activity in C57B1/6 mice. PCB-induced CTL suppression occurs coincident with significant elevation of plasma glucocorticoid (GC) levels (> 500 ng/ml). Since GC elevation can cause immune suppression, this study was conducted to determine if TCDD-induced CTL suppression is correlated with elevation of plasma corticosterone (CS), the major GC in mice. Single oral doses of TCDD (2.5-40 micrograms/kg) induced a dose-dependent suppression of CTL activity with a calculated 50% immunosuppressive dose (ID50) occurring at 7.2 micrograms/kg. When total lytic units (LU)/spleen were calculated, the ID50 was 2.8 micrograms/kg. In contrast, plasma CS levels were not significantly altered at doses below 40 micrograms/kg. These data suggest that TCDD-induced CTL suppression is not dependent on CS elevation. The direct effect of TCDD on CTL generation was tested by adding TCDD at 10(-13)-10(-9) M to in vitro mixed lymphocyte-tumor cell (MLTC) cultures. No alteration of CTL activity was observed after 5 days of culture at any TCDD concentration. In contrast, CS alone significantly suppressed CTL activity in vitro. CS-induced CTL suppression in vitro was neither enhanced nor inhibited by the presence of TCDD. These results suggest that TCDD causes CTL suppression in vivo by a mechanism that does not involve CS.
先前的研究表明，2,3,7,8-四氯二苯并对二恶英（TCDD）是一种强效免疫抑制化合物。在我们实验室中，已证明TCDD和结构相关的多氯联苯（PCBs）可抑制C57B1/6小鼠的同种异体抗原特异性细胞毒性T淋巴细胞（CTL）活性。PCB诱导的CTL抑制与血浆糖皮质激素（GC）水平显著升高（>500 ng/ml）同时发生。由于GC升高可导致免疫抑制，因此进行本研究以确定TCDD诱导的CTL抑制是否与小鼠主要的GC——血浆皮质酮（CS）升高相关。单次口服TCDD（2.5 - 40微克/千克）可诱导CTL活性出现剂量依赖性抑制，计算得出的50%免疫抑制剂量（ID50）为7.2微克/千克。当计算总裂解单位（LU）/脾脏时，ID50为2.8微克/千克。相比之下，在剂量低于40微克/千克时，血浆CS水平无显著变化。这些数据表明，TCDD诱导的CTL抑制不依赖于CS升高。通过在体外混合淋巴细胞 - 肿瘤细胞（MLTC）培养物中添加10^(-13) - 10^(-9) M的TCDD来测试TCDD对CTL生成的直接影响。在任何TCDD浓度下培养5天后，未观察到CTL活性有改变。相比之下，单独的CS在体外显著抑制CTL活性。TCDD的存在既未增强也未抑制CS在体外诱导的CTL抑制。这些结果表明，TCDD在体内通过一种不涉及CS的机制导致CTL抑制。
