Deficient Tryptophan Catabolism along the Kynurenine Pathway Reveals That the Epididymis Is in a Unique Tolerogenic State
Deficient Tryptophan Catabolism along the Kynurenine Pathway Reveals That the Epididymis Is in a Unique Tolerogenic State
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DOI：
10.1074/jbc.m110.172114
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发表时间：
2011-03-11
影响因子：
4.8
通讯作者：
Drevet, Joel R.
中科院分区：
文献类型：
--
作者：
Jrad-Lamine, Aicha;Henry-Berger, Joelle;Drevet, Joel R.
吲哚胺2，3-双加氧酶（IDO）是犬尿氨酸途径中色氨酸催化的第一个酶和限速酶。有趣的是，与IDO由促炎细胞因子（例如干扰素）诱导的大多数其他组织相比，IDO在哺乳动物附睾中组成性且高度表达。为了深入了解IDO在哺乳动物附睾生理学中的作用，我们研究了野生型和Ido 1（-/-）缺陷小鼠。在Ido 1（-/-）动物的附睾头中，IDO活性的缺乏没有被其他的Dahan分解代谢酶补偿，导致犬尿氨酸产量的损失。IDO的缺乏在附睾头中产生了炎症状态，如通过各种炎症标志物的增加的积累所揭示的。IDO的缺乏也增加了附睾头的色氨酸含量，并产生了平行的附睾头蛋白质含量的增加，作为蛋白酶体活性不足的结果。令人惊讶的是，IDO表达的缺乏对总体男性生育力没有明显影响，但确实诱导异常精子的数量和百分比的高度显著增加。与野生型小鼠相比，这些变化与附睾液中白色血细胞计数的显著降低一致。这些数据支持IDO在附睾精子质量控制中发挥迄今为止未被怀疑的作用，涉及缺陷精子的泛素化及其随后的去除。
Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme of tryptophan catabolism through the kynurenine pathway. Intriguingly, IDO is constitutively and highly expressed in the mammalian epididymis in contrast to most other tissues where IDO is induced by proinflammatory cytokines, such as interferons. To gain insight into the role of IDO in the physiology of the mammalian epididymis, we studied both wild type and Ido1(-/-)-deficient mice. In the caput epididymis of Ido1(-/-) animals, the lack of IDO activity was not compensated by other tryptophan-catabolizing enzymes and led to the loss of kynurenine production. The absence of IDO generated an inflammatory state in the caput epididymis as revealed by an increased accumulation of various inflammation markers. The absence of IDO also increased the tryptophan content of the caput epididymis and generated a parallel increase in caput epididymal protein content as a consequence of deficient proteasomal activity. Surprisingly, the lack of IDO expression had no noticeable impact on overall male fertility but did induce highly significant increases in both the number and the percentage of abnormal spermatozoa. These changes coincided with a significant decrease in white blood cell count in epididymal fluid compared with wild type mice. These data provide support for IDO playing a hitherto unsuspected role in sperm quality control in the epididymis involving the ubiquitination of defective spermatozoa and their subsequent removal.