Pallardy M J, House R V, Dean J H
Department of Cellular and Molecular Toxicology, Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
Mol Pharmacol. 1989 Jul;36(1):128-33.
Previous studies in this laboratory have demonstrated that exposure of mice to the carcinogenic polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene results in suppression of both humoral and cell-mediated immunity. This suppression is unaccompanied by any significant alteration in splenic lymphocyte subpopulation composition, suggesting that the immune deficit was due to a modulation of lymphocyte function. Additional studies implicated the T helper lymphocyte as the probable target for 7,12-dimethylbenz[a]anthracene-induced immunosuppression, apparently through an inhibition of interleukin 2 production. The purpose of the present study was to examine the mechanism of 7,12-dimethylbenz[a]anthracene-induced T lymphocyte dysfunction at the molecular level and to determine the consequences of 7,12-dimethylbenz[a]anthracene exposure on the interleukin 2 pathway. In vitro exposure of Con A-activated splenocytes to 7,12-dimethylbenz[a]anthracene resulted in suppression of the mitogenic response, suppressed interleukin 2 production, and reduced the expression of the high affinity receptor for interleukin 2. In contrast, expression of the low affinity interleukin 2 receptor was not affected. In addition, interleukin 2-dependent lymphoblasts and long term cultured splenocytes exhibited a dose-dependent decrease in proliferation following in vitro exposure to 7,12-dimethylbenz[a]anthracene. These results suggest that 7,12-dimethylbenz[a]anthracene-induced immunosuppression may be mediated, at least in part, through the interleukin 2/interleukin 2 receptor pathway.
本实验室之前的研究表明，将小鼠暴露于致癌性多环芳烃7,12-二甲基苯并[a]蒽会导致体液免疫和细胞介导免疫受到抑制。这种抑制并未伴随脾淋巴细胞亚群组成的任何显著改变，这表明免疫缺陷是由于淋巴细胞功能的调节所致。进一步的研究表明，T辅助淋巴细胞可能是7,12-二甲基苯并[a]蒽诱导免疫抑制的靶点，显然是通过抑制白细胞介素2的产生。本研究的目的是在分子水平上研究7,12-二甲基苯并[a]蒽诱导的T淋巴细胞功能障碍的机制，并确定7,12-二甲基苯并[a]蒽暴露对白细胞介素2途径的影响。将伴刀豆球蛋白A激活的脾细胞在体外暴露于7,12-二甲基苯并[a]蒽会导致有丝分裂反应受到抑制、白细胞介素2的产生受到抑制，并降低白细胞介素2高亲和力受体的表达。相比之下，低亲和力白细胞介素2受体的表达不受影响。此外，白细胞介素2依赖性淋巴母细胞和长期培养的脾细胞在体外暴露于7,12-二甲基苯并[a]蒽后，增殖呈剂量依赖性下降。这些结果表明，7,12-二甲基苯并[a]蒽诱导的免疫抑制可能至少部分是通过白细胞介素2/白细胞介素2受体途径介导的。
