JAK/STAT and the GATA factor Pannier control hemocyte maturation and differentiation in Drosophila

The lymph gland is the major site of hematopoiesis in Drosophila. During late larval stages three types of hemocytes are produced, plasmatocytes, crystal cells, and lamellocytes, and their differentiation is tightly controlled by conserved factors and signaling pathways. JAK/STAT is one of these pathways which have essential roles in vertebrate and fly hematopoiesis. We show that Stat has opposing cell-autonomous and non-autonomous functions in hemocyte differentiation. Using a clonal approach we established that loss of Stat in a set of prohemocytes in the cortical zone induces plasmatocyte maturation in adjacent hemocytes. Hemocytes lacking Stat fail to differentiate into plasmatocytes, indicating that Stat positively and cell-autonomously controls plasmatocyte differentiation. We also identified the GATA factor pannier (pnr) as a downstream target of Stat. By analyzing the phenotypes resulting from clonal loss and over-expression of pnr in lymph glands, we find that Pnr is positively regulated by Stat and specifically required for the differentiation of plasmatocytes. Stat and Pnr represent two essential factors controlling blood cell maturation in the developing lymph gland and exert their functions both in a cell-autonomous and non-cell-autonomous manner.     

Tissue communication in a systemic immune response of Drosophila

Several signaling pathways, including the JAK/STAT and Toll pathways, are known to activate blood cells (hemocytes) in Drosophila melanogaster larvae. They are believed to regulate the immune response against infections by parasitoid wasps, such as Leptopilina boulardi, but how these pathways control the hemocytes is not well understood. Here, we discuss the recent discovery that both muscles and fat body take an active part in this response. Parasitoid wasp infection induces Upd2 and Upd3 secretion from hemocytes, leading to JAK/STAT activation mainly in hemocytes and in skeletal muscles. JAK/STAT activation in muscles, but not in hemocytes, is required for an efficient encapsulation of wasp eggs. This suggests that Upd2 and Upd3 are important cytokines, coordinating different tissues for the cellular immune response in Drosophila. In the fat body, Toll signaling initiates a systemic response in which hemocytes are mobilized and activated hemocytes (lamellocytes) are generated. However, the contribution of Toll signaling to the defense against wasps is limited, probably because the wasps inject inhibitors that prevent the activation of the Toll pathway. In conclusion, parasite infection induces a systemic response in Drosophila larvae involving major organ systems and probably the physiology of the entire organism.     

细胞因子信号转导负调控因子家族

JAK／STAT是细胞因子发挥生物学功能的重要信号转导途径。作为抑制JAK／STAT途径的蛋白质－细胞因子信号转导负调控因子SOCS家族,目前已知有8个成员,细胞因子通过JAK／STAT通路调节该家族蛋白表达。近年来基因敲除在SOCS研究领域的广泛应用初步阐明了SOCS在体内的生物学功能。     

用于治疗类风湿性关节炎的JAK 抑制剂

类风湿性关节炎是一种临床常见的慢性自身免疫性疾病,发病过程中滑膜组织及细胞分泌的大量细胞因子通过不同途径激活JAK/STAT 信号通路,并导致病变。因此,选择JAK 抑制剂针对性地阻断JAK/STAT 通路,可达到改善类风湿性关节炎病理过程的目的。概述JAK/STAT 信号通路的组成与结构、功能与机制以及在类风湿性关节炎发病过程中的作用,并着重介绍若干具代表性的已上市和尚处于临床及临床前研究阶段的JAK 抑制剂在类风湿性关节炎治疗中的应用研究。     

当归多糖对K62细胞EpoR介导的信号转导通路研究

目的:研究当归多糖(APS)对K562细胞中EpoR介导的JAK2/STAT5信号转导通路的影响.方法:实验分为APS组(200mg/L APS)及阴性对照组(常规培养),两组细胞培养24h加入5×103IU/L Epo刺激,Western blot法检测Epo刺激不同时间后K562细胞核、浆蛋白中JAK2、STAT5的表达变化;免疫沉淀法检测其活性改变;采用免疫细胞化学技术和荧光显微镜观察其分布.结果:两组细胞培养24h加入Epo继续刺激对JAK2的表达影响不大,但APS组JAK2的活性较阴性对照组增强;Epo继续刺激K562细胞核中STAT5的表达及活性APS组都较阴性对照组增强.结论:APS在促进正常造血过程中,可能在EpoR介导的信号转导过程中增强JAK2、STAT5的酪氨酸磷酸化发挥重要作用.     

白血病抑制因子与胚胎干细胞

白血病抑制因子对细胞的生长和分化有多种作用,通过与其受体结合传导信号,gp130与LIF受体β链的结合激活JAK激酶(JAK1和JAK2),JAK激酶磷酸化STAT信号转录子,STAT3的磷酸化对于阻止体外培养的干细胞的分化具有十分重要的作用。     

JAK／STAT signaling regulates tissue outgrowth and male germline stem cell fate in Drosophila

In multicellular organisms, biological activities are regulated by cell signaling. The various signal transduction pathways regulate cell fate, proliferation, migration, and polarity. Miscoordination of the communicative signals will lead to disasters like cancer and other fatal diseases. The JAK/STAT signal transduction pathway is one of the pathways, which was first identified in vertebrates and is highly conserved throughout evolution. Studying the JAK/STAT signal transduction pathway in Drosophila provides an excellent opportunity to understand the molecular mechanism of the cell regulation during development and tumor formation. In this review, we discuss the general overview of JAK/STAT signaling in Drosophila with respect to its functions in the eye development and stem cell fate determination.     

JAK/STAT信号转导通路与淋巴瘤的形成

JAK/STAT信号转导通路的异常激活在多种淋巴瘤的发生发展中发挥重要作用. 该信号通路的抑制剂在淋巴瘤的靶向治疗中具有良好的应用前景．本文对JAK/STAT信号通路与淋巴瘤发生、发展的最新研究进展进行综述,重点介绍该信号通路中各种JAK激酶及STAT分子的异常突变类型,以及它们在各类淋巴瘤形成中的作用、调控机制及其靶向治疗策略,旨在为该信号通路在淋巴瘤发生发展中的影响及作用机制的进一步研究提供借鉴．     

Ovarian carcinoma cells inhibit T cell proliferation: suppression of IL-2 receptor beta and gamma expression and their JAK-STAT signaling pathway

Deficient T cell immune function and intracellular signaling in cancer patients may result from effects of tumors or their products on lymphocytes. Recently, it was demonstrated that several ovarian carcinoma cell lines could produce soluble factors that inhibited T cell proliferation. The aim of this study is to assess the effect of supernatants from 3 ovarian carcinoma cell lines (OVCAR3, CAOV3, SKOV3) on signal transduction elements that are linked to the IL-2R and its JAK-STAT pathway. A profound inhibition of proliferation, lower level of IFN-gamma and higher level of IL-10 gene expression were observed when CD8+ T cells were co-cultured with supernatants from 3 ovarian carcinoma cell lines. Cell cycle studies on inhibited CD8+ T cells showed most of them were growth arrested in G0/G1 phase. Western blot analysis showed that tumor supernatants suppressed expression of JAK3 and tyrosine phosphorylation of STAT5. JAK1 was not altered and the inhibition of STAT3 only appeared in OVCAR3 cells. Tumor supernatants also partially blocked induction of IL-2R beta and gamma chains expression. These findings suggest that ovarian carcinoma cells may suppress T cell proliferation through inhibition IL-2 dependent signaling pathways, which may be a mechanism of ovarian carcinoma induced immunosuppression.     

罗氟司特对脓毒症炎症大鼠炎症因子及淋巴细胞的调控机制分析

摘要 目的：探究罗氟司特通过JAK/STAT途径对脓毒症炎症大鼠炎症因子及淋巴细胞的调控机制分析。方法：将54只SD大鼠随机分为正常组（n=18）,模型组（n=18）和罗氟司特组（n=18）,正常组正常喂养,模型组和罗氟司特组建立脓毒症大鼠模型。模型组和罗氟司特组腹膜内注射0.9 %的氯化钠和罗氟司特。干预7 d后,对大鼠取样。测定灌洗液中炎症细胞的数量、JAK和STAT-3的蛋白、AST和ALT、IL-6和TNF-α的mRNA表达。结果：在观察的7 d中,正常组大鼠均存活,生存率高于模型组和罗氟司特组（P<0.05）,罗氟司特组生存率高于模型组（P<0.05）。与正常组相比,模型组和罗氟司特组术后症状评分均增加（P<0.05）,罗氟司特组术后症状评分低于模型组（P<0.05）。模型组和罗氟司特组的miRNA-218表达低于正常组（P<0.05）,而罗氟司特组高于模型组（P<0.05）;模型组和罗氟司特组淋巴细胞,中性粒细胞和单核细胞总数,JAK和STAT-3的蛋白质表达,AST、ALT、IL-6和TNF-α水平高于正常组（P<0.05）,罗氟司特组上述指标低于模型组（P<0.05）。结论：罗氟司特通过JAK / STAT途径阻断miRNA-218表达,抑制促炎性细胞因子IL-6和TNF-α的表达,减轻脓毒症炎症的机制和肝脏损害并改善多发性脓毒症的生存率。