雌激素上调吲哚胺2,3-双加氧酶表达的分子机制

It is well known from the recent literature and from our preliminary experiment results that estrogens can induce upregulation of Indoleamine 2,3-dioxygenase (IDO),yet the upregulation mechanisms have not been reported. Based on the former research achievement,we intend to investigate molecular mechanisms involved in estrogen-induced upregulation of IDO with Western blot and co-pulldown assays. According to the latest research findings in dendritic cell, IDO expression inversely correlates with the expression of suppressors of cytokine signaling 3（SOCS3）,and high expression of IDO and SOCS3 cannot exist side by side（nature immunology,2011）. However, high expression of IDO and SOCS3 coexist at materno-fetal interface. In this programme,we try to explain why the expression of SOCS3 does not decrease when the expression of IDO is upregulated. The program is a basic research on maternofetal immune tolerance and the purpose of the programme is to locate suitable molecular targets for preventing or treating autoimmune diseases. The main contents are organized as the following: (1)By upregulating of TGF-β and IFN-γ,and by activating Src family kinases,estrogens can upregulate the expression of IDO. (2) Acting through estrogen receptor( ER) binding to SOCS3, estrogens can prevent proteasomal degradation of IDO.(3) Estrogens may lead to high-level coexpression of IDO and SOCS3.

从文献报道和本项目的预实验结果可以确定雌激素可上调IDO的表达，然而，雌激素上调IDO表达的机制却未见报道。我们在前期研究的基础上拟用Western blot和co-pulldown 等技术来研究雌激素上调IDO 表达的机制；据最新研究结果，IDO的表达与SOCS3的表达成反比，IDO与SOCS3的高表达不可以同时存在（nature immunology,2011），然而，在母胎界面IDO与SOCS3的高表达确实并存。本研究试图用新的机制解释雌激素如何上调IDO表达，与此同时，SOCS3的表达却没有减少或降低。本项目为母胎耐受提供基础研究，为治疗自身免疫性疾病提供新的分子靶点。具体研究内容如下：(1) 雌激素通过上调TGF-β和IFN-γ及活化Src等途径而上调IDO的表达；(2)雌激素通过其受体与SOCS3分子结合，阻止IDO的降解；(3) 雌激可致SOCS3与IDO的高表达并存。

从文献报道和本项目的预实验结果可以确定雌激素可上调IDO 的表达，然而，雌激素上调IDO 表达的机制却未见报道。我们用Western blot 和免疫荧光等技术来研究雌激素上调IDO 表达的机制。结果显示，雌激素至少可通过三方面上调IDO 的表达：雌激素通过上调TGF-β的表达来上调IDO的表达；雌激素通过上调IFN-γ的表达来上调IDO蛋白的表达；雌激素通过下调SOCS3的表达来上调IDO蛋白的表达。本项目的研究为治疗免疫性不孕、自身免疫性疾病及移植排斥反应提供新的分子靶点。