RIG-I and dsRNA-Induced IFNβ Activation

Except for viruses that initiate RNA synthesis with a protein primer (e.g., picornaviruses), most RNA viruses initiate RNA synthesis with an NTP, and at least some of their viral _pppRNAs remain unblocked during the infection. Consistent with this, most viruses require RIG-I to mount an innate immune response, whereas picornaviruses require mda-5. We have examined a SeV infection whose ability to induce interferon depends on the generation of capped dsRNA (without free 5′ tri-phosphate ends), and found that this infection as well requires RIG-I and not mda-5. We also provide evidence that RIG-I interacts with poly-I/C in vivo, and that heteropolymeric dsRNA and poly-I/C interact directly with RIG-I in vitro, but in different ways; i.e., poly-I/C has the unique ability to stimulate the helicase ATPase of RIG-I variants which lack the C-terminal regulatory domain.     

Interferon-α (IFNα) neurotoxicity

Clinical studies indicate that increased central nervous system (CNS) interferon-alpha (IFNα) is associated with cognitive dysfunction in a wide variety of conditions. This has perhaps been best studied in HIV-associated neurocognitive disorders (HAND). These findings on IFNα neurotoxicity have been corroborated in animal studies. Probably the best demonstration of the neurotoxicity of IFNα was through the use of a mouse model of HAND, where it was shown that blocking IFNα with neutralizing antibodies prevented behavioral deficits and associated histopathological effects. In vitro studies have demonstrated a dose dependent, detrimental effect of IFNα on neuronal dendrites. Development of therapeutics that block IFNα may prove to be an effective treatment of HAND and other inflammatory conditions where there is increased CNS IFNα.     

干扰素(IFN)与AIDS疫苗

阐述了干扰素（IFN）在重组AIDS疫苗中的作用与意义。为AIDS的基因免疫治疗提出了新的研究方向。     

Inhibiting autophagy potentiates the anticancer activity of IFN1@/IFNα in chronic myeloid leukemia cells

IFN1@ (interferon, type 1, cluster, also called IFNα) has been extensively studied as a treatment for patients with chronic myeloid leukemia (CML). The mechanism of anticancer activity of IFN1@ is complex and not well understood. Here, we demonstrate that autophagy, a mechanism of cellular homeostasis for the removal of dysfunctional organelles and proteins, regulates IFN1@-mediated cell death. IFN1@ activated the cellular autophagic machinery in immortalized or primary CML cells. Activation of JAK1-STAT1 and RELA signaling were required for IFN1@-induced expression of BECN1, a key regulator of autophagy. Moreover, pharmacological and genetic inhibition of autophagy enhanced IFN1@-induced apoptosis by activation of the CASP8-BID pathway. Taken together, these findings provide evidence for an important mechanism that links autophagy to immunotherapy in leukemia.     

分离出自身免疫疾病治疗关键的IFN受体

以色列Weizmam研究所Menachem Rubinstein等成功地分离出Ⅰ型干扰素(IFN)受体。一旦在细胞膜蛋白中结合IFN,细胞就活化,发挥防御病毒感染的能力。这种活性是非常有益的,但另一方面,IFN2如果过剩,免疫系统就会攻击自身组织,屡发自身免疫疾病。因此如使用受体,去除过多的IFN2,就能开发新的自身免疫疾病的治疗方法。     

应用FISH评估IFN治疗CML的疗效

应用间期荧光原位杂交技术(FISH)评估干扰素(IFN)治疗慢性粒细胞白血病(CML)有较好疗效。主持这一技术(FISH)的山东济宁市第一人民医院的李强医生等,为探讨FISH检测CML IFN治疗体内残留Ph阳性细胞的效果,采取间期FISH的方法,对7例未治疗CML病者和17例IFN-α-2b长期治疗CML病者进行治疗,并检测体内Ph阳性细胞的变化。     

IFN α2b抗流感病毒的作用

用流感病毒攻击小鼠建立动物模型,观察了重组干扰素α2b抗流感病毒的作用。小鼠采用滴鼻和腹腔注射途径分别给予40μL干扰素α2b,取40μL致死剂量(LD50)流感病毒攻击小鼠,观察IFNα2b抗流感病毒的效果。结果显示,干扰素可提高小鼠生存率。可见干扰素具有抗流感病毒的作用。     

Interaction of IFNλR1 with TRAF6 regulates NF-κB activation and IFNλR1 stability

IFNλR1 is a member of the class II cytokine receptor family, and it associates with IL‐10R2 to form a functional receptor complex, IFNλR. This receptor complex transduces signals from IFNλs (IFNλ1, IFNλ2, and IFNλ3), promoting antiviral and antiproliferative activities similar to those of type I IFNs. In an effort to further understand signal transduction through IFNλR1, we used bioinformatics analysis and identified a tumor necrosis factor receptor‐associated factor 6 (TRAF6)‐binding motif in the intracellular domain of IFNλR1. In subsequent immunoprecipitation and GST pull‐down assays, IFNλR1 was shown to immunoprecipitate with TRAF6 and was pulled down by GST‐TRAF6. Endogenous IFNλR1 and TRAF‐6 interaction implies that these proteins really interact in the cells. This interaction was abrogated upon mutation of the TRAF6‐binding motif in IFNλR1. Furthermore, the interaction between IFNλR1 and TRAF6 inhibited TRAF6‐induced NF‐κB activation, likely due to a reduction in TRAF6 autoubiquitination. Moreover, co‐expression of IFNλR1 with TRAF6 significantly increased the stability of IFNλR1, thereby prolonging its half‐life and enhancing its steady‐state level in cultured cells. J. Cell. Biochem. 113: 3371–3379, 2012. © 2012 Wiley Periodicals, Inc.     

生产高纯度干扰素(IFN)的新苗头

IFN的作用愈来愈引起人们的高度注视,一是它的抗病毒作用;二是它的抗癌作用,有所谓“妙药”之称,有掀起“工程菌合成IFN”之热。目的是生产大量人体IFN供临床之用。为获取IFN之应用,除保证量的供应外,还有两个重要之点:一是IFN的专异性,即人体IFN仅能用之于人,这样,使IFN应用就受到一定限制;二是IFN高度的     

IFN和PDS合剂体内抗流感病毒的作用

观察了IFN与PDS合剂的体内抗病毒效果。首先排除IFN和PDS对动物的毒性作用 ,再以不同剂量的单剂和合剂给小鼠用药。用流感强毒株对小鼠进行攻击 ,同时以利巴韦林和正常小鼠作为对照。通过对动物死亡率、肺部病变的病理组织学检查结果进行比较 ,合剂组效果明显好于单剂组 ,且有剂量效应关系。上述结果表明 ,IFN和PDS合剂可明显减轻流感病毒感染过程中的肺组织病变 ,可用于流行性感冒的治疗。     

干扰素(IFN)研究在我国的发展

干扰素(IFN)是由诱生剂在高等生物细胞中诱导生成的一种糖蛋白,具有抗病毒、抗肿瘤和调节免疫系统的基本作用,在临床上得到实际应用,主要有三种类型即IFN-d、IFN-β、IFN-T。直接从高等生物提取它有一定的局限性,产量有限,价格比黄金还要贵的多。为此通过基因工程办法能使微生物具有合成这三种IFN的能力,这已在国内外取得成功,并有新发展,有的已商品化生产,其产品应用于临床取得较好效果,有的还在继续探究之中,如IFN的分子改造、提高IFN的活性以及扩大新的应用范围等等。我国科研人员经过十来年的努力为微生物合成IFN打下了扎实的基础,使研究工作取得突破性进展,应该说,这是我国基因工程研究最早地取得“工程干扰素”这一重要成果。现在,通过基因工程构建的“工程微生物”能合成不同类型的[FN,有的已进入中试生产阶段。这里着重把近年来IFN基因工程研究所取得的成果包括IFN-r和IL-2、IFN-α、IFN-β与α及其作用以及IFN蛋白工程等方面作些简介。 IFN-r(免疫干扰素)具有较强的免疫调节和细胞抑制活性。     

生产高纯度干扰素(IFN)的新苗头

IFN的作用愈来愈引起人们的高度注视,一是它的抗病毒作用;二是它的抗癌作用,有所谓“妙药”之称,有掀起“工程菌合成IFN”之热。目的是生产大量人体IFN供临床之用。为获取IFN之应用,除保证量的供应外,还有两个重要之点:一是IFN的专异性,即人体IFN仅能用之于人,这样,使IFN应用就受到一定限制;二是IFN高度的     

美MIT用玻璃纤维附着动物细胞高效生产IFN

美国马萨诸塞理工学院附属生物技术工艺工程中心王所长(Daniel I.C.Wang)在美国微生物学会生物工程讨论会上报道,把附着性的培养哺乳动物细胞附着在玻璃纤维上可提高干扰素(IFN)的产量。 王氏纤维玻璃床的培养罐的产量每小时由基因重组的中国田鼠卵巢细胞产生7万I.U.(国际单位)的IFN。     

人白细胞IFN—α的临床应用前景

<正>人干扰素以其极高的特异生物学活性已广泛用于临床。最近的研究表明凡是生长很快的组织(胚胎、肿瘤)中均能检测到干扰素和组织凝集素。胚胎中的干扰素主要为2.4～8万道尔顿的IFN—α和β结构干扰素(βs)。并证实组织凝集素系干扰素的拮抗物,从而推断生长因子、干扰素和组织凝集素对细胞生长的调节具有极为重要的作用,其中干扰素的主要生物学功能除抗病毒外就是对细胞的负调节协调生长作用。     

泛素特异性蛋白酶18抑制IFNα抗HBV活性但并不抑制IFNλ抗HBV的活性（英文）

干扰素α(IFN-α)是临床最常用的抗乙型肝炎病毒(HBV)药物之一。泛素特异性蛋白酶18(USP18)被证实是抑制IFN-α抗HBV活性的因子,但USP18是否对干扰素λ(IFN-λ)抗HBV有影响还尚未可知。为了明确USP18对IFNλ抗HBV活性的影响,本研究以Hep G2. 2. 15细胞作为乙肝体外模型,采用脂质体转染法分别向细胞转染p EGFP-USP18、PEGFP-N1经48 h,再经IFN-α和IFN-λ处理24 h,分为阴性对照组﹑USP18过表达+IFN-α组﹑空载组+IFN-α组﹑USP18过表达+IFN-λ组﹑空载组+IFN-λ组。采用Western印迹、RT-q PCR和ELISA检测各组的乙肝病毒标志物、STAT1/p STAT1和下游的干扰素刺激基因(ISGs)的表达。结果显示,与阴性对照组和空载组相比,USP18蛋白在过表达组明显升高(P 0. 05),过表达细胞模型构建成功;在IFN-α处理的两组中,空载组中HBs Ag、HBe Ag、HBc Ag及HBV-DNA的表达均低于USP18过表达组,差异有统计学意义(P 0. 05)。而IFN-λ处理组中,乙肝病毒标志物的差异不明显。在IFN-α处理组中,空载组的ISG15、Mx A、IFIT1和p STAT1表达均高于USP18过表达组,差异有统计学意义(P 0. 05),而在IFN-λ处理组中ISGs和p STAT1的表达无明显差异。上述结果证实,USP18可通过抑制JAK/STAT信号通路的激活来减弱IFN-α抗HBV的活性。研究还证实,IFN-λ可发挥抗HBV的作用,USP18不通过JAK/STAT信号通路抑制其抗HBV活性。     

Genome-wide genetic associations with IFNγ response to smallpox vaccine

Smallpox is a deadly and debilitating disease that killed hundreds of millions of people in the past century alone. The use of Vaccinia virus-based smallpox vaccines led to the eradication of smallpox. These vaccines are remarkably effective, inducing the characteristic pustule or "take" at the vaccine site in >97?% of recipients, and inducing a wide spectrum of long-lasting humoral and cellular immune responses. The mechanisms behind inter-individual vaccine-response variability are likely to involve host genetic variation, but have not been fully characterized. We report here the first smallpox vaccine response genome-wide association study of over 1,000 recent recipients of Dryvax(?). The data presented here focus on cellular immune responses as measured by both production of secreted IFNγ and quantitation of IFNγ secreting cells by ELISPOT assay. We identified multiple significant SNP associations in genes (RASA1, ADRA1D, TCF7L1, FAS) that are critical components of signaling pathways that directly control lymphocyte IFNγ production or cytotoxic T cell function. Similarly, we found many associations with SNPs located in genes integral to nerve cell function; findings that, given the complex interplay between the nervous and immune systems, deserve closer examination in follow-up studies.