吲哚胺-2,3-双加氧酶及其在肿瘤方面免疫调节的研究进展

吲哚胺-2,3-双加氧酶是催化色氨酸沿犬尿氨酸分解代谢的限速酶,在哺乳动物组织和细胞中广泛表达.色氨酸耗竭及其代谢产物是调节免疫抑制和免疫耐受的重要机制,在多种生理和病理状态中发挥重要的作用.因此,吲哚胺-2,3-双加氧酶在器官移植、自身免疫性疾病和肿瘤等方面的治疗也成了研究的热点.     

吲哚胺2,3双加氧酶在病毒感染中的作用

吲哚胺2,3双加氧酶(indoleamine 2,3-dioxygenase,IDO)是色氨酸犬尿氨酸代谢途径的限速酶.IDO在抗病毒免疫中起重要作用,他能介导IFN-γ病毒及有免疫调节和致免疫耐受功能.本文就其在抗病毒免疫方面作一综述.     

吲哚胺2，3-双加氧酶及CD25在食管癌组织中的表达及临床意义

目的检测吲哚胺2,3-双加氧酶（IDO）及CD25在人食管癌及癌旁组织中的表达,了解其与食管癌临床病理特征之间的关系及在肿瘤免疫逃避中的作用。方法应用免疫组织化学法检测60例食管癌及12例癌旁组织中IDO及CD25的表达。结果IDO及CD25在食管癌组织的表达明显高于癌旁组织（P〈0．05）;IDO及CD25在癌组织中的高表达具有相关性（r=0．958,P〈0．01）;IDO与肿瘤的分化程度、浸润深度、淋巴结转移相关（P均〈0．05）。结论IDO及CD25在癌组织中均高表达,IDO的过表达可能参与了食管癌的发生发展,促进了肿瘤细胞的浸润和淋巴结转移。     

吲哚胺2,3-双加氧酶——多种肝病中发挥双刃剑作用的重要介质

吲哚胺2,3-双加氧酶(IDO)是一种重要的免疫调节酶,可降解哺乳动物必需氨基酸色氨酸水平,通过犬尿氨酸途径催化起始和限速步骤并产生多种代谢产物参与免疫应答。IDO一方面对微环境发挥免疫抑制作用,导致感染、肿瘤细胞免疫逃逸等;另一方面,对细菌、寄生虫等病原体同样发挥抑制作用,一定程度上保护机体免受病原体的侵害。因此,IDO被认为是在多种肝脏疾病发生发展中具有双刃剑作用的重要介质。本文就IDO在病毒性肝炎、肝纤维化、肝硬化、肝癌、肝棘球蚴病中的最新研究进展作一综述。     

布地奈德上调支气管哮喘小鼠肺组织IDO、抑制气道炎症和气道高反应性的研究

目的 研究布地奈德对急性支气管哮喘(简称哮喘)模型小鼠肺组织吲哚胺-2,3双加氧酶(IDO)表达、气道炎症和气道高反应性的干预作用.方法 18只SPF级BALB/c小鼠随机分为正常组、哮喘组、布地奈德组.卵白蛋白(OVA)致敏和激发建立哮喘模型.末次激发24 h后,测定气道对乙酰胆碱的反应性,HE染色观察气道炎症细胞浸润,ELISA法检测血清总IgE、OVA特异性IgE(OVA-sIgE)以及支气管肺泡灌洗液(BALF) Th2细胞因子(IL-4和IL-13).Western blot检测肺组织IDO蛋白表达.结果 正常组小鼠气道阻力随乙酰胆碱浓度增加仅轻度增加,哮喘组气道阻力较正常组显著增高,布地奈德组气道阻力较哮喘组显著下降(P＜0.05);哮喘组血清总IgE和OVA-sIgE、BALF炎症细胞总数和嗜酸粒细胞分类计数、Th2细胞因子水平较正常组显著增高,布地奈德组炎症指标较哮喘组显著降低(P＜0.05);哮喘组肺组织IDO)较正常组显著下降,布地奈德组肺组织IDO较哮喘组显著增高(P＜0.05).结论 布地奈德抑制急性哮喘模型气道炎症和气道高反应性,可能与上调肺组织IDO有关.     

吲哚胺-2,3双加氧酶、白细胞介素-10及白细胞介素-17变化与慢性阻塞性肺疾病的相关性

目的探讨慢性阻塞性肺疾病(COPD)稳定期患者血中吲哚胺-2,3双加氧酶(IDO)、白细胞介素(IL)-10及IL-17变化及其临床意义。方法检测33例COPD稳定期患者及21例健康对照组外周血中IDO mRNA、IL-17及IL-10水平。结果与健康对照组相比,COPD稳定期患者IDO mRNA及IL-10下降(P0.05),IL-17升高(P0.05)。结论 COPD稳定期患者中IDO减少,诱导IL-17分泌增加,IL-10分泌减少,IDO的减少可能参与了COPD慢性炎症的发生发展,提高机体树突细胞IDO的分泌有望为COPD的治疗开辟新的思路。     

吲哚胺2,3-双加氧酶参与调控寄生虫与宿主免疫互作关系的研究进展

吲哚胺2,3-双加氧酶(indoleamine 2,3-dioxygenase,IDO)是一种重要的免疫调节酶,主要通过耗竭色氨酸(tryp-tophan,Trp)和产生多种代谢产物来调节免疫效应.近年来,对IDO免疫功能的研究大多局限在肿瘤、自身免疫性疾病等领域,而在寄生虫病中的研究相对较少,尤其是寄生虫与宿主免疫互...     

吲哚胺2,3-二加氧酶抑制剂对慢性脑低灌注大鼠认知功能损害的行为学改善

目的观察使用吲哚胺2,3-二加氧酶(IDO)抑制剂后慢性脑低灌注大鼠认知功能损害的行为学改善,及血犬尿氨酸(KYN)、犬尿喹啉酸(KYNA)水平的变化。方法雄性Wistar大鼠30只,随机分为假手术组,对照组和IDO抑制剂组,各10只,后2组采用改良的永久性双侧颈总动脉结扎术制作慢性脑低灌注大鼠模型。Morris水迷宫检测大鼠空间学习与记忆能力变化,高效液相色谱-荧光检测法检测血KYN、KYNA的水平,免疫组织化学检测大鼠海马CA1区IFN-γ、TNF-α表达。结果与假手术组比较,对照组IFN-γ、TNF-α表达明显升高(P<0.05);与对照组比较,IDO抑制剂组大鼠第4、5天逃避潜伏期缩短,平台象限游泳距离百分比增加,KYN[(15.33±0.90)μmol/L vs(1.69±0.94)μmol/L]及KYNA[(39.51±3.81)μmol/L vs(25.66±6.80)μmol/L]水平明显降低(P<0.05),但IFN-γ、TNF-α表达无显著差异(P>0.05)。结论 IDO抑制剂不影响炎性因子表达,但可减少血KYN及KYNA表达,可改善慢性脑低灌注所致的认知功能损害的空间学习及记忆能力。     

吲哚胺2,3-二氧化酶对HepG2细胞生物学行为影响的研究

吲哚胺2,3-二氧化酶(indoleamine 2,3-dioxygenase,IDO)是细胞内一种含亚铁血红素的酶,是肝脏以外惟一可催化色氨酸分子中吲哚环氧化裂解,从而沿犬尿酸途径进行分解代谢的限速酶,可将色氨酸分解为L-犬尿酸、吡啶甲酸和喹啉酸等多种代谢物.     

吲哚胺2,3-二氧化酶对HepG2细胞生物学行为影响的研究

吲哚胺2,3-二氧化酶(indoleamine 2,3-dioxygenase,IDO)是细胞内一种含亚铁血红素的酶,是肝脏以外惟一可催化色氨酸分子中吲哚环氧化裂解,从而沿犬尿酸途径进行分解代谢的限速酶,可将色氨酸分解为L-犬尿酸、吡啶甲酸和喹啉酸等多种代谢物.     

Decreased indoleamine 2,3-dioxygenase expression in dendritic cells and role of indoleamine 2,3-dioxygenase-expressing dendritic cells in immune thrombocytopenia

Indoleamine 2,3-dioxygenase (IDO) expression in dendritic cells (DCs) can induce or maintain peripheral immune tolerance. Impaired IDO-mediated tryptophan catabolism has been observed in autoimmune diseases. In order to investigate the effects of IDO-mediated tryptophan catabolism and IDO-expressing DCs in immune thrombocytopenia, the concentrations of kynurenine were detected by high-pressure liquid chromatography. The expressions of IDO were analyzed by flow cytometry and western blot analysis. The effects of IDO(+) DCs stimulated with CTLA-4-Ig on T cells proliferation and activation, lymphocyte apoptosis, and Tregs were measured by flow cytometry. We found that the expression of IDO in DCs of immune thrombocytopenia (ITP) patients was significantly decreased. CTLA-4-Ig significantly increased the expression of functional IDO in DCs of ITP patients. IDO(+) DCs stimulated with CTLA-4-Ig suppressed T cells proliferation and activation, promoted lymphocyte apoptosis, and increased the percentage of Tregs. These results suggest that decreased IDO expression in DCs may play a critical role in ITP. CTLA-4-Ig successfully corrected the disorder of IDO expression in ITP. IDO(+) DCs stimulated with CTLA-4-Ig inhibited immune responses by an IDO-dependent mechanism. Increasing the expression and activity of IDO in DCs might be a promising therapeutic approach for ITP.     

Immunological role of indoleamine 2,3-dioxygenase in rat liver allograft rejection and tolerance

Background and Aim:  Indoleamine 2,3-dioxygenase (IDO) is expressed in the placenta and plays an essential role in maternal tolerance. Recent data showed that giving IDO inhibitor blocked liver allograft tolerance. However, the immunological role of IDO in rat liver allograft models has not been characterized. In the present study, the time-course of IDO expression and the localization of IDO were analyzed to address the role of IDO in the induction of tolerance.
Methods:  Rat orthotopic liver transplantations (OLT) were performed and IDO gene expression of OLT livers was analyzed. Immunohistochemistry was used to evaluate the localization of IDO-expressed cells in the liver.
Results:  The IDO gene was detected in the allogeneic liver graft at the acute phase but the signal could not be detected when these OLT rats were treated with cyclosporinee A. The time-course of IDO gene expression in liver grafts of the spontaneous tolerant OLT model revealed that the IDO mRNA was expressed in both the rejection phase and the induction phase of tolerance, but the signal was gradually lowered during the maintenance phase of tolerance. Immunohistochemistry confirmed that the IDO protein was detected in antigen-presenting cells but not in hepatocytes.
Conclusion:  Our results demonstrated that IDO is induced in antigen-presenting cells of rat liver allografts under drug-free status, suggesting that indirect or direct recognition of donor antigen and further T-cell activation may be inhibited. IDO may act as a local immunosuppressive molecule to protect transplanted cells, tissues and organs from immune attack.     

Indole peroxygenase activity of indoleamine 2,3-dioxygenase

The heme enzyme indoleamine 2,3-dioxygenase (IDO) was found to catalyze the oxidation of indole by H(2)O(2), with generation of 2- and 3-oxoindole as the major products. This reaction occurred in the absence of O(2) and reducing agents and was not inhibited by superoxide dismutase or hydroxyl radical scavengers, although it was strongly inhibited by l-Trp. The stoichiometry of the reaction indicated a one-to-one correspondence for the consumption of indole and H(2)O(2). The (18)O-labeling experiments indicated that the oxygen incorporated into the monooxygenated products was derived almost exclusively from H(2)(18)O(2), suggesting that electron transfer was coupled to the transfer of oxygen from a ferryl intermediate of IDO. These results demonstrate that IDO oxidizes indole by means of a previously unrecognized peroxygenase activity. We conclude that IDO inserts oxygen into indole in a reaction that is mechanistically analogous to the "peroxide shunt" pathway of cytochrome P450.     

Induction of pulmonary indoleamine 2,3-dioxygenase by interferon.

Pulmonary indoleamine 2,3-dioxygenase [indoleamine: oxygen 2,3-oxidoreductase(decyclizing)] has been found to be induced (30- to 100-fold) in the mouse after a single intraperitoneal administration of bacterial endotoxin [Yoshida, R. & Hayaishi, O. (1978) Proc. Natl. Acad. Sci. USA 75, 3998-4000] or during in vivo virus infection [Yoshida, R., Urade, Y., Tokuda M. & Hayaishi, O. (1979) Proc. Natl. Acad. Sci. USA 76, 4084-4086]. In the present study, an in vitro system with mouse lung slices was developed in which bacterial endotoxin (5 micrograms/ml)produced an induction (approximately 10-fold) of indoleamine 2,3-dioxygenase. The endotoxin was substituted by interferon from mouse L cells or mouse brain. The pulmonary enzyme activity increased almost linearly for 48 hr after addition of mouse interferon (10(4) units/ml) to lung slices. Interferon from mouse L cells or mouse brain produced a 10- to 15-fold increase in the enzyme activity, whereas that from human leukocytes was all but ineffective. The effect also was observed using highly purified L-cell interferon, prepared by poly(U) affinity column chromatography. When interferon was treated either by heat, alpha-chymotrypsin, or anti-interferon serum, such increase in the enzyme activity was diminished essentially to the same extent as seen in the antiviral activity. The increase in the enzyme activity was blocked when actinomycin D or cycloheximide was added to the slices before interferon treatment. These results suggest that the enzyme induction was produced by interferon and not by possible contaminants in the interferon preparations.     

Interleukin-4 inhibits indoleamine 2,3-dioxygenase expression in human monocytes

Indoleamine 2,3-dioxygenase (IDO), a flavin-dependent enzyme that catalyzes the conversion of tryptophan to kynurenine, is induced in peripheral blood mononuclear cells by interferon-gamma (IFN gamma). Interleukin-4 (IL-4) is a cytokine that modulates the functional properties of monocytes/macrophages, and we investigated the effects of IL-4 on IDO. We showed that IL-4 inhibited the induction of IDO mRNA and IDO activity by IFN gamma in human monocytes. The inhibitory effect was evident with as little as 2 U/mL of IL-4. These results provide the first evidence that a cytokine can provide a negative signal for IDO expression and that IL-4 can influence the catabolism of tryptophan.     

狼疮肾炎患者肾组织中吲哚胺2,3-双加氧酶的表达及意义

目的检测Ⅳ型狼疮肾炎（LN）患者肾组织中吲哚胺2，3-双加氧酶（IDO）的表达情况及其与肾间质浸润炎细胞的增殖和肾小管-间质病理损害程度之间的关系。方法采用免疫组织化学染色法观察正常肾组织和Ⅳ型LN患者肾组织IDO的表达情况，并进一步分析其表达与肾间质浸润核增殖抗原（PCNA）阳性淋巴细胞数及肾小管-间质（TIL）病理损害程度之间的相关关系。结果正常肾组织未检测到IDO表达，而在Ⅳ型LN肾小管上皮细胞IDO的表达阳性，并且LN肾小管上皮细胞表达IDO的阳性强度与TIL PCNA＋浸润细胞数及TIL病理损害程度呈显著负相关。结论IDO在Ⅳ型LN肾小管上皮细胞中呈高表达，并与TIL浸润细胞增殖情况及TIL病理变化呈负相关，提示IDO可能参与LNTIL病理损害过程。