Saas P, Bohuon C, Pallardy M
Laboratoire d'Immunotoxicologie et de Cancérogenèse, Faculté de Pharmacie Paris-Sud, Chatenay-Malabry, France.
J Toxicol Environ Health. 1996 Nov;49(4):371-87. doi: 10.1080/009841096160772.
Polycyclic aromatic hydrocarbons are ubiquitous environmental contaminants known to be carcinogenic as well as immunosuppressive. Structure-activity studies have demonstrated that modifications in the number of methyl groups of benzanthracenic compounds lead to major changes in their biological activities such as induction of tumors. In the present study, we investigated the immunosuppressive effects of three benzanthracene derivatives differing by number or position of methyl radicals. 7,12-Dimethylbenz[a]anthracene, 12-methylbenz[a]anthracene, and 7-methylbenz[a]anthracene were tested for their ability to inhibit T-cell proliferation. For this purpose, we employed an in vitro activation model utilizing concanavalin A (ConA) or anti-CD3 monoclonal antibody (anti-CD3 mAb) to induce proliferation of murine T-lymphocytes from B6C3F1 mice. The three compounds inhibited splenocyte proliferation stimulated with anti-CD3 mAb, whereas DMBA and 12-MBA, but not 7-MBA, inhibited ConA-induced lymphoproliferation. Results concerning parameters involving interleukin-2 (IL-2) were correlated with those obtained for lymphoproliferation. IL-2 production and number of IL-2 receptors (IL-2R) per cell were inhibited by the three molecules tested, except for IL-2 production following ConA activation of cells treated with 7-MBA. Only DMBA profoundly affected IL-2 responsiveness, suggesting that this compound may inhibit both G0 to G1 and G1 to S transitions of the cell cycle. Addition of exogenous cytokines such as IL-1 and IL-6 with IL-2, or IL-2 alone, suggested that, for the three compounds tested, IL-1 and IL-6 production are not involved in benz[a]anthracene-induced immunosuppression. These results demonstrate that methylation at both 7 and 12 positions of the benzanthracene ring significantly enhances immunosuppression. In addition, DMBA may act on signal transduction mediated by the T-cell receptor (TCR) and the IL-2R, while this is not the case for 7-MBA and 12-MBA.
多环芳烃是普遍存在的环境污染物，已知具有致癌性和免疫抑制作用。构效关系研究表明，苯并蒽化合物甲基数量的改变会导致其生物活性发生重大变化，如诱导肿瘤。在本研究中，我们调查了三种因甲基基团数量或位置不同的苯并蒽衍生物的免疫抑制作用。测试了7,12 - 二甲基苯并[a]蒽、12 - 甲基苯并[a]蒽和7 - 甲基苯并[a]蒽抑制T细胞增殖的能力。为此，我们采用了一种体外激活模型，利用刀豆蛋白A（ConA）或抗CD3单克隆抗体（抗CD3 mAb）诱导B6C3F1小鼠的鼠T淋巴细胞增殖。这三种化合物抑制了抗CD3 mAb刺激的脾细胞增殖，而7,12 - 二甲基苯并[a]蒽（DMBA）和12 - 甲基苯并[a]蒽（12 - MBA），但不是7 - 甲基苯并[a]蒽（7 - MBA），抑制了ConA诱导的淋巴细胞增殖。涉及白细胞介素 - 2（IL - 2）的参数结果与淋巴细胞增殖的结果相关。除了用7 - MBA处理的细胞经ConA激活后的IL - 2产生外，测试的这三种分子均抑制了IL - 2的产生和每个细胞的IL - 2受体（IL - 2R）数量。只有DMBA深刻影响IL - 2反应性，表明该化合物可能同时抑制细胞周期从G0到G1以及从G1到S的转变。添加外源性细胞因子如IL - 1和IL - 6与IL - 2，或单独添加IL - 2，表明对于测试的这三种化合物，IL - 1和IL - 6的产生不参与苯并[a]蒽诱导的免疫抑制。这些结果表明，苯并蒽环7位和12位的甲基化显著增强了免疫抑制作用。此外，DMBA可能作用于由T细胞受体（TCR）和IL - 2R介导的信号转导，而7 - MBA和12 - MBA则不然。
