McMillan Brian J, McMillan Susanne N, Glover Ed, Bradfield Christopher A
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706, USA.
J Biol Chem. 2007 Apr 27;282(17):12590-7. doi: 10.1074/jbc.M611446200. Epub 2007 Mar 2.
The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) causes numerous and diverse toxic events via activation of the aryl hydrocarbon receptor, including atrophy of the thymus. Exposure to TCDD induces acute thymocyte cell loss, which occurs concomitantly with proliferation arrest and premature emigration of triple negative (TN; CD4(-), CD8(-), CD3(-)) T cell progenitors. In this report, we demonstrate that TCDD exposure results in dysregulation of KLF2 (Kruppel-like factor 2) expression in developing thymocytes. The Klf2 gene encodes an Sp1-like zinc finger transcription factor that functions as a central regulator of T lymphocyte proliferation and trafficking. During normal thymocyte development, KLF2 is expressed exclusively in CD4 and CD8 single positive T cells and promotes a nonproliferative, promigratory phenotype. In mice exposed to TCDD, however, the Klf2 gene is prematurely expressed in TN thymocytes. Administration of a 100 microg/kg dose of TCDD results in a approximately 15-fold induction of KLF2 as early as the TN2 (CD44(+), CD25(+)) stage of development and immediately precedes acute cell loss in the TN3, TN4, and double positive (CD4(+), CD8(+)) cell stages. Induction of KLF2 occurs within 12 h of TCDD exposure and is fully dependent on expression of the aryl hydrocarbon receptor. In addition, TCDD exposure alters the expression of several factors comprising the KLF2 regulon, including Edg1/S1P(1), beta(7) integrin, CD52, Cdkn2d (cyclin-dependent kinase inhibitor 2D), s100a4, and IL10R alpha. These findings indicate that the pollutant TCDD interferes with early thymopoeisis via ectopic expression of the KLF2 regulon.
环境污染物2,3,7,8-四氯二苯并对二恶英（TCDD，二恶英）通过激活芳烃受体引发众多不同的毒性事件，包括胸腺萎缩。暴露于TCDD会导致急性胸腺细胞丢失，这与三阴性（TN；CD4(-)、CD8(-)、CD3(-)）T细胞祖细胞的增殖停滞和过早迁出同时发生。在本报告中，我们证明TCDD暴露会导致发育中的胸腺细胞中KLF2（Kruppel样因子2）表达失调。Klf2基因编码一种Sp1样锌指转录因子，它是T淋巴细胞增殖和运输的核心调节因子。在正常胸腺细胞发育过程中，KLF2仅在CD4和CD8单阳性T细胞中表达，并促进非增殖、促迁移表型。然而，在暴露于TCDD的小鼠中，Klf2基因在TN胸腺细胞中过早表达。给予100μg/kg剂量的TCDD会导致KLF2在发育的TN2（CD44(+)、CD25(+)）阶段最早诱导约15倍，紧接着在TN3、TN4和双阳性（CD4(+)、CD8(+)）细胞阶段出现急性细胞丢失。KLF2的诱导在TCDD暴露后12小时内发生，并且完全依赖于芳烃受体的表达。此外，TCDD暴露会改变构成KLF2调控子的几种因子的表达，包括Edg1/S1P(1)、β(7)整合素、CD52、Cdkn2d（细胞周期蛋白依赖性激酶抑制剂2D）、s100a4和IL10Rα。这些发现表明污染物TCDD通过KLF2调控子的异位表达干扰早期胸腺生成。
