Kudo Yoshiki, Hara Tetsuaki, Katsuki Takafumi, Toyofuku Aya, Katsura Yuki, Takikawa Osamu, Fujii Tsuneo, Ohama Koso
Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Hum Reprod. 2004 May;19(5):1222-30. doi: 10.1093/humrep/deh218. Epub 2004 Apr 7.
Expression of the tryptophan catabolizing enzyme, indoleamine 2,3-dioxygenase, in the mouse placenta has been shown to be critical in preventing immunological rejection of the fetal allograft. To clarify the physiological importance of indoleamine 2,3-dioxygenase in human pregnancy, we have studied how the expression of this enzyme changes during decidualization of human endometrium at both the cell and tissue level.
The level of indoleamine 2,3-dioxygenase mRNA expression (determined by RT-PCR) was higher in decidual than in endometrial tissue. Uterine decidual tissue in ectopic pregnancy similarly showed increased mRNA expression. Immunohistochemistry demonstrated that indoleamine 2,3-dioxygenase protein immunoreactivity was found in glandular epithelium and in stromal cells. The intensity of this immunoreactivity was increased in decidualized tissue. In a cell culture model, the level of indoleamine 2,3-dioxygenase mRNA was suppressed specifically by progesterone-induced decidualization of isolated endometrial stromal cells. Indoleamine 2,3-dioxygenase protein abundance (determined by Western blot) was also decreased by progesterone-induced decidualization. However interferon-gamma, a potent stimulator of indoleamine 2,3-dioxygenase gene expression, increased the level of indoleamine 2,3-dioxygenase mRNA and protein in both non-decidualized and in decidualized cells. Indoleamine 2,3-dioxygenase activity (determined by measuring the concentration of tryptophan and its indoleamine 2,3-dioxygenase catabolite, kynurenine) was also decreased by progesterone-induced decidualization but enhanced following interferon-gamma treatment. Expression of other interferon-gamma inducible genes (STAT1 and tryptophanyl-tRNA synthetase) showed the same pattern as that of indoleamine 2,3-dioxygenase in tissue samples, but was not changed by decidualization in the cell culture model.
These data suggest that despite suppression by progesterone, indoleamine 2,3-dioxygenase expression in endometrial stromal cells may increase during decidualization due to stimulation by interferon-gamma secreted by infiltrating leukocytes.
色氨酸分解代谢酶吲哚胺2,3-双加氧酶在小鼠胎盘中的表达已被证明对防止胎儿同种异体移植物的免疫排斥至关重要。为了阐明吲哚胺2,3-双加氧酶在人类妊娠中的生理重要性，我们在细胞和组织水平上研究了该酶在人子宫内膜蜕膜化过程中的表达变化。
蜕膜组织中吲哚胺2,3-双加氧酶mRNA表达水平（通过逆转录聚合酶链反应测定）高于子宫内膜组织。异位妊娠中的子宫蜕膜组织同样显示mRNA表达增加。免疫组织化学显示，在腺上皮和基质细胞中发现了吲哚胺2,3-双加氧酶蛋白免疫反应性。这种免疫反应性的强度在蜕膜化组织中增加。在细胞培养模型中，吲哚胺2,3-双加氧酶mRNA水平被孕酮诱导的分离子宫内膜基质细胞蜕膜化特异性抑制。孕酮诱导的蜕膜化也降低了吲哚胺2,3-双加氧酶蛋白丰度（通过蛋白质印迹法测定）。然而，吲哚胺2,3-双加氧酶基因表达的有效刺激剂γ干扰素增加了未蜕膜化和蜕膜化细胞中吲哚胺2,3-双加氧酶mRNA和蛋白的水平。孕酮诱导的蜕膜化也降低了吲哚胺2,3-双加氧酶活性（通过测量色氨酸及其吲哚胺2,3-双加氧酶分解代谢物犬尿氨酸的浓度来测定），但γ干扰素处理后活性增强。其他γ干扰素诱导基因（信号转导和转录激活因子1以及色氨酸-tRNA合成酶）的表达在组织样本中与吲哚胺2,3-双加氧酶表现出相同的模式，但在细胞培养模型中不受蜕膜化影响。
这些数据表明，尽管受到孕酮的抑制，但由于浸润白细胞分泌的γ干扰素的刺激，子宫内膜基质细胞中吲哚胺2,3-双加氧酶的表达在蜕膜化过程中可能会增加。
