PI3K信号通路对T细胞发育、活化、增殖、分化及支气管哮喘的作用

T细胞是参与支气管哮喘发病的重要效应细胞,而磷脂酰肌醇-3-激酶(PI3K)是T细胞的重要信号转导分子。PI3K信号通过影响双阴性细胞的β-选择而影响T细胞的成熟,还通过激活PKB、Rac等信号途径而参与T细胞的活化、分化。同时,PI3K通过参与Th1/Th2失衡的调节,嗜酸粒细胞、肥大细胞的黏附、脱颗粒等而参与支气管哮喘气道炎症反应。     

1,25-二羟维生素D3与支气管哮喘

支气管哮喘的免疫机制受多种因素的调节,其中涉及到Th1/ Th2 平衡紊乱等因素.目前已知1,25-二羟维生素D3对于Th1细胞起主导作用的疾病中有着重要意义,但其对于Th2细胞起主导作用的疾病如支气管哮喘的作用目前还没有足够的研究.本文首先描述了1,25-二羟维生素D3对于哮喘气道炎症的影响,然后介绍了其对于CD4+调节T细胞的两个主要亚群:自然调节性T 细胞尤其是获得性调节性T 细胞的作用,接着介绍了1,25-二羟维生素D3对于树突状细胞DC的影响和作用,以及其对于T细胞迁移方面的影响.了解1,25-二羟维生素D3在支气管哮喘中的作用及免疫调节机制,有助于开拓哮喘治疗的新方法.     

磷脂酰肌醇3激酶信号转导途径及在支气管哮喘中的作用

磷脂酰肌醇3激酶（PI3K）信号转导通路是参与支气管哮喘（哮喘）发病机制的一条重要受体信号转导途径。在哮喘患者体内,通过这一途径影响气道平滑肌的增殖并对T细胞受体和协同刺激因子受体CD28介导的T细胞的分化、生存、活化和细胞因子的产生起了关键性的作用。这一机制的研究旨在阐明PI3K信号转导通路在哮喘气道重构中的作用,以及相应的拮抗剂的研究,为哮喘的治疗提供了新方向。     

PI3K/Akt信号通路在HIV感染中的研究进展

[摘要]　磷脂酰肌醇3-激酶（phosphoinositide 3-kinase, PI3K）/蛋白激酶B（protein kinase B, PKB,普遍写作Akt）信号通路参与调控多种细胞功能，与多种疾病的发生密切相关。PI3K/Akt信号通路在HIV感染过程中也发挥重要作用，包括调节T细胞、线粒体功能，促进HIV复制，再激活潜伏HIV以及维持病毒储存库。因此，探索PI3K/Akt信号通路在HIV感染中的作用机制具有重要意义，针对PI3K/Akt的靶向治疗可能在抗HIV中发挥关键作用。本文对PI3K/Akt信号通路与HIV感染的相关研究进行综述，旨在为HIV的治疗提供新的思路与靶点。     

磷脂酰肌醇3激酶信号转导途径及在支气管哮喘中的作用

磷脂酰肌醇3激酶（PI3K）信号转导通路是参与支气管哮喘（哮喘）发病机制的一条重要受体信号转导途径。在哮喘患者体内，通过这一途径影响气道平滑肌的增殖并对T细胞受体和协同刺激因子受体CD28介导的T细胞的分化、生存、活化和细胞因子的产生起了关键性的作用。这一机制的研究旨在阐明PI3K信号转导通路在哮喘气道重构中的作用，以及相应的拮抗剂的研究，为哮喘的治疗提供了新方向。     

磷脂酰肌醇3-激酶途径对支气管哮喘大鼠气道平滑肌细胞增殖的影响及罗红霉素的干预作用

气道蘑塑是支气管哮喘(简称哮喘)的重要病理特征,气道平滑肌细胞(airway smooth muscle cells,ASMCs)增生和肥大在哮喘气道重塑中发挥了重要作用[1].磷脂酰肌醇3-激酶(phosphoinositide 3-kinases,PI3 K)途径是介导ASMCs增殖重要信号转导途径[2].罗红霉素是新一代大环内酯类抗生素,初步研究结果表明,罗红霉素能影响哮喘气道重塑,但具体机制尚不明确.本研究通过复制大鼠慢性哮喘模型,研究PI3K的重要下游信号分子Akt、p70S6K及cyclinD1活性变化,并给予PI3K特异性抑制剂渥曼青霉素(wortmannin)及罗红霉素干预,探讨PI3K信号途径在哮喘ASMCs增殖中的作用及罗红霉素对哮喘气道重塑的影响,进一步揭示哮喘的发病机制及有效的干预措施.     

Th17细胞及其在支气管哮喘发病中的作用

Th17细胞是一类新型的CD4+T细胞,STAT3、RORγt和RORα等参与了其分化调控.最近,大量研究表明,Th17及其相关的细胞因子在支气管哮喘中起着重要的作用,参与了气道炎症、气道重塑以及气道高反应性.     

PI3K/Akt信号通路与肝纤维化

PI3K/AKT信号通路可以通过调控基因表达,从而在细胞的存活、分化、生长、运动和凋亡等多种生理和病理过程中起到重要作用。尤其在肝纤维化的进展中,此信号通路发挥了重要的调节作用。本文将对目前有关PI3K/AKT信号通路在参与肝纤维化形成中,如何调控细胞外基质的降解、影响HSC的活化及调节肝窦毛细血管化等作用机制作一综述。这些资料不仅可以揭示相关疾病条件下,多个细胞与信号因子之间复杂的相互作用机制,而且能够突出通过阻断PI3K/AKT信号通路可以保护和治疗肝纤维化这一潜在的临床意义。     

辅助性T细胞在支气管哮喘发病机制中的作用

支气管哮喘(简称哮喘)是一种由多种细胞和细胞因子参与的免疫失衡性的变态反应性疾病,调节性T细胞是近10年来发现的一类在哮喘发病中起重要作用的T淋巴细胞[1].本文研究了哮喘患者Th3等辅助性T细胞亚群的数量和功能的变化,旨在研究Th3等辅助性T细胞在哮喘发病机制中的作用.     

基于miRNA表达谱解析细粒棘球蚴病患者体内Th17/Treg失衡机制

目的　观察细粒棘球蚴病患者血清微小RNA（miRNA）表达水平、探讨miRNA对辅助性T 细胞17（Th17）/调节性T细胞（Treg）失衡的影响,以阐明细粒棘球蚴慢性感染并长期致病的机制。方法　提取细粒棘球蚴病患者与健康对照者血清总RNA,采用Illumina测序平台进行高通量测序。分别采用miRBase数据库和miRDeep2工具进行已知miRNA注释和新miRNA预测,并进行差异分析。采用miRanda软件和TargetScan软件分别预测差异表达miRNA靶基因后取交集,进行基因本体（GO）富集分析以及京都基因和基因组百科全书（KEGG）通路分析。在差异表达变化倍数居前20位的miRNA中,匹配可靶向决定Th17细胞和Treg细胞生成的关键转录因子（RORC和FOXP3）或重要调控通路（PI3K⁃Akt和mTOR通路）相关基因的miRNA。结果　细粒棘球蚴病患者与健康对照血清中共有53个差异表达miRNA,其中47个上调表达miRNA、6个下调表达miRNA。GO富集分析显示,差异表达miRNA功能涉及DNA转录翻译、细胞成分、细胞形态、神经发育及代谢分解等过程。KEGG富集分析显示,这些差异表达miRNA靶基因涉及的主要信号通路包括MAPK、PI3K⁃Akt、mTOR等信号通路。在差异表达变化倍数居前20位的miRNA中,有3个潜在靶向调控RORC的miRNA、15个潜在靶向PI3K⁃Akt、mTOR信号通路的miRNA。结论　细粒棘球蚴感染后可使患者血清miRNA表达谱出现明显改变,差异表达miRNA可能通过靶向Th17/Treg关键转录因子或PI3K⁃Akt、mTOR通路而导致Th17/Treg免疫失衡,进而利于细粒棘球蚴在宿主体内长期寄生并慢性致病。     

PI3K在CD_3mAb活化T细胞信号转导中的作用

目的探讨磷脂酰肌酶-3激酶（PI3K）在CD3mAb活化T细胞信号转导途径中的作用。方法分离获取健康人外周血单个核细胞（PBMC）,用不同浓度的PI3K特异性抑制剂LY294002处理后再用CD3mAb活化T细胞。0、6、12、24、48、72h后检测总T细胞CD69分子的表达及IL-2表达情况,培养10d后计数总T细胞的增殖情况。结果LY294002呈浓度依赖性地抑制总T细胞CD69的表达、IL-2的产生和T细胞增殖。结论PI3K参与CD3mAb诱导T淋巴细胞活化的信号转导途径,对T细胞的充分活化必不可少。     

维生素A在支气管哮喘信号转导通路作用方面的研究进展

维生素A能通过对支气管哮喘(简称哮喘)相关的磷脂酰肌醇-3激酶/效应分子Akt信号转导通路的调节阻止哮喘气道平滑肌细胞的迁移,抑制气道的高反应性,改善气道的重塑;通过对核因子κB(NF-κB)信号转导通路的调节抑制哮喘气道的炎症;通过对酪氨酸蛋白激酶转录激活因子信号转导通路的作用影响Th1/Th2细胞的平衡.从信号转导通路水平来研究维生素A对哮喘的作用将能更好更系统的阐明哮喘的本质,也有助于开辟哮喘新的治疗方法.     

Integrin-dependent cell growth and survival are mediated by different signals in thyroid cells

Cell adhesion to extracellular matrix regulates proliferation and survival of several cell types including epithelial thyroid cells. Activation of integrin receptors by binding to extracellular matrix generates a complex cell type-dependent signaling. Adhesion to extracellular matrix induces proliferation and survival in primary cultures of thyroid cells and induces survival in immortalized human thyrocytes. In this study we demonstrate that in immortalized human thyrocyte cells, adhesion to immobilized fibronectin (FN) stimulates DNA synthesis and proliferation through the p21Ras/MAPK pathway, whereas cell survival is mediated by phosphatidylinositol 3-kinase (PI3K) signal pathway. Integrin activation by immobilized FN induced phosphorylation of pp125 focal adhesion kinase and paxillin and induced the formation of focal adhesion kinase/Grb-2/Sos complex. Western blot and in vitro kinase assay demonstrated the activation of Ras and the p44/p42 MAPK/ERK1/2. Inhibition of p21Ras activity and inhibition of MAPK enzymatic activity completely arrested cell growth but did not induce cell death. Integrin activation by cell adhesion to FN also induced activation of PI3K. Inhibition of PI3K enzymatic activity induced apoptosis demonstrated by annexin V-binding assay and loss of cellular DNA content. These results demonstrate that in thyroid cells adhesion to FN regulates proliferation through the p21Ras/MAPK signal pathway, whereas integrin-mediated cell survival is mediated by PI3K.     

钙/钙调神经磷酸酶-活化T细胞核因子信号通路与T细胞活化及支气管哮喘关系的研究进展

钙/钙调神经磷酸酶-活化T细胞核因子信号通路作为T细胞内重要的生物信号转导通路,在T细胞活化中起到调节枢纽的作用,与Th细胞的分化及多种细胞因子的产生有密切关系;而T细胞的浸润和活化在支气管哮喘(简称哮喘)气道慢性炎症及气道重塑的发生、发展过程中具有重要的意义,因此,钙/钙调神经磷酸酶-活化T细胞核因子信号通路可能与哮喘的发生有密切关系,其在哮喘T细胞活化机制中的研究对于揭示哮喘的发病机制和治疗有重要的意义.     

IL-2- and IL-15-induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes

We examined functional status, activation mechanisms, and biologic role of the mTORC1 signaling pathway in malignant CD4(+) T cells derived from the cutaneous T-cell lymphoma (CTCL). Whereas the spontaneously growing CTCL-derived cell lines displayed persistent activation of the TORC1 as well as the PI3K/Akt and MEK/ERK pathways, the IL-2-dependent cell lines activated the pathways in response to IL-2 and IL-15 but not IL-21. Activation of mTORC1 and MEK/ERK was nutrient dependent. The mTORC1, PI3K/Akt, and MEK/ERK pathways could also be activated by IL-2 in the primary leukemic, mitogen-preactivated CTCL cells. mTORC1 activation was also detected in the CTCL tissues in the lymphoma stage-dependent manner with the highest percentage of positive cells present in the cases with a large cell transformation. Rapamycin inhibited mTORC1 signaling and suppressed CTCL cell proliferation but showed little effect on their apoptotic rate when used as a single agent. Activation of the mTORC1, PI3K/Akt, and MEK/ERK pathways was strictly dependent on the Jak3 and Jak1 kinases. Finally, mTORC1 activation was transduced preferentially through the PI3K/Akt pathway. These findings document the selective gammac-signaling cytokine-mediated activation of the mTORC1 pathway in the CTCL cells and suggest that the pathway represents a therapeutic target in CTCL and, possibly, other T-cell lymphomas.     

Phosphoinositide 3-kinase delta inhibitor as a novel therapeutic agent in asthma

Multiple signal transduction pathways are involved in airway inflammation with one of the key signalling pathways being phosphoinositide 3-kinase (PI3K). Numerous components of the PI3K pathway play an important role in the expression and activation of inflammatory mediators, inflammatory cell recruitment, immune cell function, airway remodelling and corticosteroid insensitivity in asthma. More recently studies exploring the specific roles of different PI3K catalytic subunit isoforms in asthma have been initiated. Several of these have highlighted the importance of p110delta isoform as a novel target for therapeutic intervention in asthma. In this review the biological role of PI3Ks, especially PI3Kdelta, are highlighted and the therapeutic potential of selective PI3Kdelta inhibitor in asthma discussed.     

Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase

The T-cell costimulatory receptors, CD28 and the inducible costimulator (ICOS), are required for the generation of follicular B helper T cells (T_FH) and germinal center (GC) reaction. A common signal transducer used by CD28 and ICOS is the phosphoinositide 3-kinase (PI3K). Although it is known that CD28-mediated PI3K activation is dispensable for GC reaction, the role of ICOS-driven PI3K signaling has not been defined. We show here that knock-in mice that selectively lost the ability to activate PI3K through ICOS had severe defects in T_FH generation, GC reaction, antibody class switch, and antibody affinity maturation. In preactivated CD4⁺ T cells, ICOS delivered a potent PI3K signal that was critical for the induction of the key T_FH cytokines, IL-21 and IL-4. Under the same settings, CD28 was unable to activate PI3K but supported a robust secondary expansion of T cells. Thus, our results demonstrate a nonredundant function of ICOS-PI3K pathway in the generation of T_FH and suggest that CD28 and ICOS play differential roles during a multistep process of T_FH differentiation.     

PI3K与支气管哮喘发作期T细胞增殖周期蛋白关系的研究进展

T细胞是支气管哮喘(简称哮喘)发病机制中的核心细胞.T细胞增殖周期异常在哮喘中发挥着重要作用.PI3K信号转导途径是T细胞内重要的信号转导途径,与细胞周期蛋白异常密切相关,其机制的研究对于哮喘的治疗有重要的意义.