Interferon stimulated gene 15 conjugates to endometrial cytosolic proteins and is expressed at the uterine-placental interface throughout pregnancy in sheep
Interferon stimulated gene 15 conjugates to endometrial cytosolic proteins and is expressed at the uterine-placental interface throughout pregnancy in sheep
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DOI：
10.1210/en.2004-1224
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发表时间：
2005-02-01
期刊：
影响因子：
4.8
通讯作者：
Johnson, GA
中科院分区：
文献类型：
--
作者：
Joyce, MM;White, FJ;Johnson, GA
干扰素刺激基因15 （ISG15）是反刍动物子宫内响应干扰素(IFN)-tau表达的一种泛素同源物，在小鼠、猪、人类和狒狒的子宫内妊娠期间也会被诱导表达。本研究检测了ISG15的表达及其与靶蛋白的结合在绵羊子宫中超过了IFNtau的分泌期。虽然ISG15 mRNA的稳态水平在怀孕第25天后下降，但ISG15在子宫内膜中持续到第120天。原位杂交和免疫细胞化学将ISG15定位于整个子宫壁至第25天，之后ISG15的表达仅限于沿母体-胎盘界面的子宫内膜基质。Western blot显示子宫内膜中存在ISG15及ISG15结合蛋白。用孕酮和IFNtau处理去卵巢羊，游离和结合的ISG15均增加。这些结果首次显示了任何物种子宫中I型IFN对ISG15功能（即与靶蛋白结合）的体内调节，并且当滋养外胚层不再产生IFNtau时，ISG15在胎盘和子宫之间的接触处表达。有趣的是，在第15-50天，II型IFNgamma的mRNA存在于子宫内膜间质室中，这可能在妊娠后期刺激ISG15的合成。我们假设ISG15不仅仅是滋养细胞IFNtau诱导的抗病毒状态的结果，而且在绵羊和其他哺乳动物的妊娠发育、着床和胎盘的进展过程中，ISG15是子宫-胎盘界面微环境的关键组成部分。
Interferon-stimulated gene 15 (ISG15) is a ubiquitin homolog expressed in uteri of ruminants in response to interferon (IFN)-tau and is also induced during pregnancy in the uteri of mice, pigs, humans, and baboons. This study examined expression of ISG15 and its conjugation to target proteins in the ovine uterus beyond the period of IFNtau secretion by the conceptus. Although steady-state levels of ISG15 mRNA decreased after d 25 of pregnancy, ISG15 persisted in endometrium through d 120. In situ hybridization and immunocytochemistry localized ISG15 across the entire uterine wall through d 25, after which expression was restricted to endometrial stroma along the maternal-placental interface. Western blots revealed ISG15 and ISG15-conjugated proteins in endometrium. Treatment of ovariectomized sheep with progesterone and IFNtau increased both free and conjugated ISG15. These results are the first to show in vivo regulation of ISG15 function (i.e. conjugation to target proteins) by a type I IFN in the uterus of any species and that ISG15 is expressed at contacts between the placenta and uterus when trophectoderm no longer produces IFNtau. Interestingly, mRNA for the type II IFNgamma was present in the endometrial stromal compartment on d 15-50, which may stimulate the synthesis of ISG15 through later pregnancy. We hypothesize that ISG15 is not merely a consequence of an antiviral state induced by trophoblast IFNtau but represents a critical component of the microenvironment at the uterine-placental interface during the progressive events of conceptus development, implantation, and placentation in sheep and perhaps other mammalian species.