Gene expression profiling of 17beta-estradiol and genistein effects on mouse thymus.
Gene expression profiling of 17beta-estradiol and genistein effects on mouse thymus.
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17β-雌二醇和金雀异黄素对小鼠胸腺影响的基因表达谱。
DOI：
10.1093/toxsci/kfi219
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Cooke,PaulS
中科院分区：
文献类型：
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作者：
Selvaraj,Vimal;Bunick,David;Finnigan-Bunick,Carrol;Johnson,RodneyW;Wang,Huixia;Liu,Lei;Cooke,PaulS
雌激素调节胸腺发育和退化，并调节免疫功能。尽管其在胸腺中的关键作用，以及在自身免疫性疾病中，雌激素影响胸腺的机制尚不清楚。我们以前曾报道雌激素性大豆异黄酮和17β-雌二醇（E2）都能诱导胸腺退化，但染料木素的作用仅部分通过雌激素受体介导。为了深入了解胸腺中雌激素作用的机制，我们使用高密度DNA阵列研究了E2（125 ng/天）和染料木素（饲料中1500 ppm）诱导的断奶小鼠胸腺基因表达的变化。我们确定了几个E2反应基因参与胸腺发育和胸腺细胞信号在选择和成熟。功能表征表明对参与转录、凋亡和细胞周期的基因的影响。这项研究还确定了几个E2调节的转录本的变化，这些转录本对维持免疫自身耐受至关重要。E2比染料木黄酮上调更多的基因，而染料木黄酮比E2下调更多的基因。虽然每个治疗调节几个基因不改变其他的，有相当大的重叠在E2和染料木素调节的基因。转录因子和细胞周期因子的变化与染料木黄酮和E2诱导的细胞增殖减少一致。如非E2反应基因的调节所示，染料木黄酮还通过非雌激素机制诱导独特的作用。染料木黄酮特异性下调CD 4辅助受体转录本与我们先前研究中染料木黄酮处理小鼠中CD 4+胸腺细胞的下降一致。这是第一项确定胸腺中E2和染料木黄酮靶基因的研究。这些发现提供了新的机制的见解，解释雌激素作用于胸腺细胞的发育，选择和成熟，以及染料木素对产前和新生儿胸腺发育和功能的影响。
Estrogen regulates thymic development and involution and modulates immune function. Despite its critical role in thymus, as well as in autoimmune disorders, the mechanism by which estrogen affects the thymus is not well understood. We previously reported that the estrogenic soy isoflavone genistein, as well as 17β-estradiol (E2), could induce thymic involution, but genistein effects were only partially mediated through estrogen receptors. To provide insights into mechanisms of estrogenic effects in the thymus, we investigated thymic gene expression changes induced by E2 (125 ng/day) and genistein (1500 ppm in feed) in weanling mice using high-density DNA arrays. We identified several E2-responsive genes involved in thymic development and thymocyte signaling during selection and maturation. Functional characterization indicated effects on genes involved in transcription, apoptosis, and the cell cycle. This study also identified changes in several E2-regulated transcripts essential to maintain immune self-tolerance. E2 upregulated more genes than genistein, while genistein downregulated more genes than E2. Though each treatment regulated several genes not altered by the other, there was considerable overlap in the genes regulated by E2 and genistein. Changes in transcription factors and cell cycle factors were consistent with decreases in cell proliferation induced by both genistein and E2. As indicated by the regulation of non-E2-responsive genes, genistein also induced unique effects through non-estrogenic mechanisms. The specific downregulation of the CD4 coreceptor transcript by genistein was consistent with the decline of CD4+thymocytes in genistein-treated mice in our previous study. This is the first study identifying E2 and genistein target genes in the thymus. These findings provide new mechanistic insights toward explaining estrogen action on thymocyte development, selection, and maturation, as well as the effects of genistein on prenatal and neonatal thymic development and function.