Laiosa Michael D, Wyman Amber, Murante Francis G, Fiore Nancy C, Staples J Erin, Gasiewicz Thomas A, Silverstone Allen E
Department of Microbiology and Immunology, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA.
J Immunol. 2003 Nov 1;171(9):4582-91. doi: 10.4049/jimmunol.171.9.4582.
Activation of the aryl hydrocarbon receptor (AHR), a basic helix-loop-helix transcription factor, in lymphocytes by the immunosuppressive environmental contaminant 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to cause thymic atrophy in every species studied. We set out to identify the specific hemopoietic cellular populations in which the AHR was activated to lead to thymic atrophy and to determine the effect of AHR activation in those cellular populations. Initially, we examined whether AHR activation in intrathymic dendritic cells could mediate TCDD-induced thymic atrophy. It was found that thymic atrophy occurred only when the AHR could be activated in the thymocytes but not hemopoietic-derived dendritic cells or other APCs. We next analyzed the effect of TCDD on the proliferation of thymocytes in vivo. There was a significant increase in the percentage of thymocytes in the G(1) phase of the cell cycle and a significant decrease in the percentage of S plus G(2)/M thymocytes, especially in the CD4(-)CD8(-)CD3(-) triple-negative intrathymic progenitor cell population 24 h after exposure to 30 micro g/kg TCDD. Furthermore, by 12 h after exposure to TCDD, we observed approximately 60% reduction of 5-bromo-2'-deoxyuridine incorporation in specific intrathymic progenitor cell populations. This reduction persisted for at least 6 days. These data indicate that intrathymic progenitor cells are direct targets of TCDD in the thymus and suggest that TCDD causes thymic atrophy by reducing entrance into cell cycle in these populations.
免疫抑制性环境污染物2,3,7,8-四氯二苯并对二恶英（TCDD）可激活淋巴细胞中的芳烃受体（AHR，一种碱性螺旋-环-螺旋转录因子），研究表明，在每个研究物种中，这种激活都会导致胸腺萎缩。我们着手确定AHR被激活从而导致胸腺萎缩的特定造血细胞群体，并确定AHR激活在这些细胞群体中的作用。最初，我们研究了胸腺内树突状细胞中的AHR激活是否能介导TCDD诱导的胸腺萎缩。结果发现，只有当AHR能在胸腺细胞中被激活时才会发生胸腺萎缩，而在造血来源的树突状细胞或其他抗原呈递细胞中则不会。接下来，我们分析了TCDD对体内胸腺细胞增殖的影响。暴露于30μg/kg TCDD 24小时后，细胞周期G1期胸腺细胞的百分比显著增加，S期加G2/M期胸腺细胞的百分比显著降低，尤其是在CD4(-)CD8(-)CD3(-)三阴性胸腺内祖细胞群体中。此外，暴露于TCDD 12小时后，我们观察到特定胸腺内祖细胞群体中5-溴-2'-脱氧尿苷掺入量减少了约60%。这种减少至少持续了6天。这些数据表明，胸腺内祖细胞是胸腺中TCDD的直接靶标，并提示TCDD通过减少这些群体进入细胞周期而导致胸腺萎缩。
