IL-27在Th1型免疫发生中的作用

IL-27是最近发现的一种与IL-12相关的细胞因子,它由抗原提呈细胞产生,通过广泛表达于各种免疫细胞表面的IL-27受体WSX-1/gp130发挥生物学效应。IL-27对Th1型免疫反应具有重要的调节作用。IL-27可以促进初始CD4 T细胞的增殖,也可以促进其向Th1细胞的分化及产生IFN-γ。而在高度Th1极化的情况下,IL-27的主要作用是限制Th1型免疫反应的强度和持续时间,从而保护机体免受过度的免疫反应的损伤。IL-27在抗感染免疫,抗肿瘤免疫及自身免疫性炎症等Th1型免疫主导的病理过程中起重要作用。     

The link between IL-23 and Th17 cell-mediated immune pathologies

IL-23--produced by dendritic cells--and Th17 cells have both been identified as major factors involved in autoimmune inflammation, yet their relationship with each other remains controversial. This review aims to describe the initial discovery of Th17 cells, their subsequent characterization as a unique T helper subset in mouse and man, as well as the mechanisms involved in regulating these cells. Finally, the roles of IL-23 in inflammatory diseases in relation to Th17 function will be discussed.     

The plasticity of human Treg and Th17 cells and its role in autoimmunity

CD4⁺ T helper cells are a central element of the adaptive immune system. They protect the organism against a wide range of pathogens and are able to initiate and control many immune reactions in combination with other cells of the adaptive and the innate immune system. Starting from a naive cell, CD4⁺ T cells can differentiate into various effector cell populations with specialized function. This subset specific differentiation depends on numerous signals and the strength of stimulation. However, recent data have shown that differentiated CD4⁺ T cell subpopulations display a high grade of plasticity and that their initial differentiation is not an endpoint of T cell development. In particular, FoxP3⁺ regulatory T cells (Treg) and Th17 effector T cells demonstrate a high grade of plasticity, which allow a functional adaptation to various physiological situations during an immune response. However, the plasticity of Treg and Th17 cells might also be a critical factor for autoimmune disease. Here we discuss the recent developments in CD4⁺ T cell plasticity with a focus on Treg and Th17 cells and its role in human autoimmune disease, in particular multiple sclerosis (MS).     

The B7–CD28/CTLA-4 costimulatory pathways in autoimmune disease of the central nervous system

The past year has seen significant advances in our understanding of the role of the B7–CD28/CTLA-4 pathway in regulating the responses of self-reactive T cells, giving impetus to manipulation of this pathway for treating human autoimmune diseases. Recent studies have demonstrated that B7–CD28 costimulation has critical roles in stimulating both the initiation and effector phases of autoimmunity and that CD28 regulates the threshold for activation of self-reactive T cells. Recent work has also revealed critical roles for CTLA-4 in limiting the extent of Th1/Th2 cell differentiation and in downregulating the responses of self-reactive T cells during both the initiation and progression of autoimmune disease.     

脑胶质瘤中Jab1和p27的表达与意义

目的 探讨Jab1和p27在脑胶质瘤中的表达、意义以及相互关系.方法 运用免疫组化方法检测70例胶质瘤和8例对照脑组织标本中Jab1、p27蛋白的表达.Western blot检测6例新鲜胶质瘤标本中相应分子的表达.结果 Jab1在对照脑组织中表达不明显,在Ⅱ、Ⅲ、Ⅳ级胶质瘤中阳性率分别为21.2%、65.4%、91.7% 三者之间的表达水平差异有统计学意义(P<0.001).p27在对照脑组织中表达明显,在Ⅱ、Ⅲ、Ⅳ级胶质瘤中阳性率分别为93.8%、53.8%、25.0%,三者之间的表达差异有统计学意义(P<0.001).Western blot结果显示Jab1与p27在胶质瘤中的表达水平与肿瘤细胞的恶性程度相关.相关分析显示:胶质瘤中Jab1蛋白表达与增殖指标Ki-67表达呈正相关,与p27蛋白表达呈负相关;p27蛋白表达与Ki-67表达呈负相关(P<0.001).结论 胶质瘤中Jab1的异常高表达可能是抑制p27表达的重要因素.Jab1与p27的异常表达可能在胶质瘤的发生发展过程中起促进作用.     

IL-6 cytokine family and signal transduction: a model of the cytokine system

The interleukin 6 (IL-6) cytokine family, which includes IL-6, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), IL-11 and cardiotrophin-1 (CT-1), exhibits pleiotropy and redundancy in biological activities. The IL-6 family cytokines exhibit a helical structure. Their receptors belong to the type 1 cytokine receptor family. The receptors of the IL-6 family cytokines share a receptor subunit, which explains one of the mechanisms of functional redundancy. In this review, we describe the general features of the IL-6 cytokine family and its signal transduction mechanisms. Many functional properties of the IL-6 family of cytokines and their receptors are general features of the cytokine system.     

Impact of IL-27p28 (rs153109) and TNF-α (rs1800629) Genetic Polymorphisms on the Progression of HCV Infection in Egyptian Patients

Background: Hepatitis C virus (HCV) is a universal health problem. HCV infection may proceed to liver fibrosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). The latest is the third leading global cause of cancer-related mortality. Cytokines including IL-27 and TNF-α play a major role as a link between innate and adaptive immunity which in turn deduct the outcome of HCV infection.

Aim: The present study examined the role of both (-964 A/G) single-nucleotide polymorphism (SNP) of IL-27p28 rs153109 and (-308 G/A) SNP of TNF-α rs1800629 on the progression of HCV infection in genotype 4a infected patients.

Patients and Methods: The patients enrolled in the study were divided into three main groups group I: 38 fibrotic patients, group II: 51 cirrhotic patients, and finally group III: 29 HCC patients. Sixteen healthy volunteers were used as controls. IL-27p28 rs153109 and TNF-α rs1800629 genotyping were performed using polymerase chain reaction-restriction fragment length polymorphism assay.

Results: There was no statistically significant difference between the studied groups regarding the IL-27p28 genotypes. However, TNF-α (-308) studied polymorphism showed a significant difference between the HCC and fibrosis group (p = 0.00), and also between the cirrhosis and fibrosis group (p = 0.031) revealing that AA genotype is the genotype of risk. Furthermore, the association found between allele frequencies of two studied SNPs and the four studied groups were non-significant.

Conclusion: TNF-α rs1800629 polymorphism is a potential genetic-susceptibility factor for HCV related cirrhosis and HCC progression.     

逆转录病毒介导IL-27基因对胰腺癌细胞在裸鼠体内的成瘤抑制作用及其机制

目的:探讨IL-27基因在人胰腺癌Aspc1细胞中的抗肿瘤作用及免疫机制。方法:以逆转录病毒为载体,采用基因转染的方法用G418梯度筛选法建立转染IL-27基因的Aspc1细胞,用RT-PCR检测其基因导入,ELISA法检测IL-27的分泌。将Aspc1/IL-27、Aspc1/LXSN和Aspc1细胞接种于裸鼠皮下,观察成瘤性、移植瘤的生长情况。10天时取3组裸鼠脾脏,用ELISA法检测3组小鼠脾细胞在Aspc1诱导下IFN-γ、TNF-α和IL-12的产生情况,乳酸脱氢酶法检测脾细胞杀伤活性。结果:成功建立稳定转染的Aspc1/IL-27细胞株,ELISA检测Aspc1/IL-27细胞培养上清中IL-27的分泌量为(121.56±6.29)pg/ml,而在Aspc1/LXSN细胞和Aspc1细胞的培养上清中未检出IL-27。IL-27基因转染组裸鼠皮下结节生长速度明显慢于接种空载体转染组及未转染组;接种Aspc1/IL-27细胞的裸鼠脾细胞可产生较水平的IFN-γ、TNF-α和IL-12等细胞因子,与接种Aspc1/LXSN细胞和Aspc1细胞组裸鼠的脾细胞相比明显增高(P0.01),接种Aspc1/IL-27细胞的裸鼠脾细胞杀伤活性显著性升高(P0.01)。结论:转染IL-27基因的裸鼠胰腺癌细胞所分泌的IL-27具有生物学活性,通过增强细胞免疫功能在裸鼠体内发挥抗肿瘤作用。     

PTEN及p27Kip1在子宫内膜癌中的研究进展

肿瘤抑制基因PTEN被称为子宫内膜的看家基因,许多学者提出PTEN基因在子宫内膜癌发生发展中起重要作用。另一个肿瘤抑制基因p27在子宫内膜癌的预后中具有重要的作用。现就PTEN 、p27基因在子宫内膜癌中的表达及其与子宫内膜癌发生、发展的关系以及在治疗和预后方面的研究进展进行综述。     

Sphingosine-1-phosphate differently regulates the cytokine production of IL-12, IL-23 and IL-27 in activated murine bone marrow derived dendritic cells

Sphingosine-1-phosphate (S1P) modulates many cell functions such as lymphocyte trafficking and signaling as well as keratinocyte proliferation. However, less is known about the specific effects of S1P on cytokine production, particularly on the interaction between dendritic cells (DCs) and keratinocytes, cell types which are crucial for the initiation and maintenance of chronic inflammatory skin diseases like atopic dermatitis or psoriasis. Especially the cytokines of the IL-12 family play a dominant role in many inflammatory diseases as they have a significant impact on T-helper cell function. In the present study we show that S1P decreased the production of the pro-inflammatory cytokines IL-12 and IL-23 in LPS-stimulated DCs via the common subunit p40 as well as in the crosstalk with activated keratinocytes. By using specific S1P receptor agonists (SEW2871, FTY720-P) and antagonist (JTE013) we identified an important role for S1P receptor 1 in the modulation of the cytokine profile. While diminishing IL-12 and IL-23 secretion, S1P enhanced IL-27 production in DCs. To elucidate the mechanism of the different impact on the IL-12 family cytokine production, we investigated the mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase (PI3K) pathways in DCs. By using specific MAPK-Inhibitors (U0126, SB202190, SP600125) we demonstrated that ERK, p38 and JNK differently regulate each pathway of each cytokine. While p38 and JNK did not seem to play a role in the modulation properties of S1P on cytokine production, ERK is at least partially involved in the S1P mediated modulation of IL-12 and IL-27. The PI3K-Inhibitor abrogated the S1P-induced decrease of IL-12 and IL-23 secretion, while it had no influence on the S1P-induced increase of IL-27 production. These data implicate, that S1P has an anti-inflammatory impact on the production of IL-12 family cytokines, indicating therapeutic potential for S1P treatment of several inflammatory diseases like psoriasis.     

Augmentation of naive,Th1 and Th2 effector CD4 Responses by IL-6, IL-1 and TNF

The role of antigen-presenting cell (APC)-derived cytokines in T cell activation is still controversial. Highly purified CD4 T cell populations of the naive and short-term Th1 and Th2 effector subsets were examined. Stimulation from anti-CD3 in the absence of APC was used to analyze directly T occurring cell-mediated effects, and the requirement for co-signaling was addressed using anti-CD28. Exogenous IL-6, IL-1 and TNF each enhanced proliferation and IL-2 secretion from naive cells, although IL-6 was most active in this regard. Peak responses, however, were obtained with IL-1 or TNF in combination with IL-6 resulting in up to 11-fold increases in IL-2 secretion. Enhanced naive T cell responses were only observed with anti-CD3 and anti-CD28, suggesting that co-signaling through surface-bound receptors was required to initiate IL-2 production. Although the cytokines enhanced naive activation, little effect was seen on differentiation into effector populations. IL-6 alone, or in combination, partially suppressed effectors secreting IFN-γ, but did not promote generation of effectors secreting IL-4. In contrast to reports on cloned cell lines, IL-6, TNF and IL-1 had enhancing activities on all cytokines elicited from already generated Th1 and Th2 effector populations. Again combinations of IL-6, TNF and IL-1 were most effective and generally required CD28 signaling. Induced responses with preexisting effector cells were far less than with naive cells and predominantly directed at augmenting IFN-γ and IL-5 secretion rather than IL-2 and IL-4. These studies show that APC-derived cytokines can promote T cell responses directly but largely after co-stimulation from accessory molecule co-receptors, that the effect is not specific for one T cell subset or cytokine, and that the naive T cell is the main target of action.     

Skp2和p27kip1与肿瘤间关系的研究进展

目的：探讨Skp2和p27kip1与恶性肿瘤发生、发展的关系。方法：查阅相关中外文献,分析Skp2和p27kip1的生物学特性和功能以及与常见恶性肿瘤的关系。结果：Skp2通过泛素蛋白酶体途径降解磷酸化的p27kip1,促使细胞由G1期进入S期,导致肿瘤的发生。结论：Skp2-p27kip1可能代表一种致癌通路,其与肿瘤的关系正受到越来越多的重视。     

曲古菌素A抑制血清诱导血管平滑肌细胞p27kip1表达的降解

目的：探讨组蛋白去乙酰化酶抑制剂曲古菌素A（TSA）对血管平滑肌细胞（VSMCs）p27kip1表达的影响和调控机制。方法:半定量逆转录聚合酶链反应（RT-PCR）检测p27kip1 mRNA水平，蛋白印迹测定p27kip1和skp2蛋白表达，荧光分光光度法测定20S蛋白酶体活性。结果:100 μg/L TSA不影响VSMCs中p27kip1的mRNA水平。100 μg/L TSA显著抑制血清诱导的p27kip1蛋白下调，并延长p27kip1蛋白的半衰期。100 μg/L TSA抑制血清诱导的skp2表达上调，且skp2表达与相应时点p27kip1蛋白呈负相关。100 μg/L TSA对20S蛋白酶体活性物无影响。结论:TSA对VSMCs的p27kip1表达调控不是在转录水平上，而是通过翻译后机制抑制血清诱导VSMCs的p27kip1蛋白降解，其机制可能与TSA抑制泛素连接酶亚单位skp2表达有关。     

14-3-3σ调控p27抑制Rat1-Akt细胞增殖

目的： 研究腺病毒介导14-3-3·σ（Ad-14-3-3·σ）对Akt过表达Rat1-Akt细胞增殖的影响，并探讨其作用是否通过调控p27而实现。 方法： 通过5-溴-2′脱氧尿嘧啶（BrdU）实验检测Ad-14-3-3·σ对Rat1-Akt细胞增殖的影响，并通过激酶分析法和免疫荧光实验探讨Ad-14-3-3·σ对p27磷酸化水平及其在细胞内定位的影响。 结果： Ad-14-3-3σ转染的细胞BrdU阳性率（45%）低于PBS处理组（100%）或Ad-β-gal转染的对照组细胞（98%）。14-3-3σ可降低磷酸化p27的水平和减少Akt介导的p27在胞浆中的定位。 结论： 转染14-3-3σ基因能抑制Akt过表达细胞株Rat1-Akt增殖，14-3-3σ通过降低Akt激酶磷酸化p27的活性，阻断Akt介导的p27胞浆错位，从而发挥其抑制Rat1-Akt细胞增殖。     

Differential production of IL-10 by T cells and monocytes of HIV-infected individuals: association of IL-10 production with CD28-mediated immune responsiveness

Immune unresponsiveness in HIV-1 infection can result from impaired signals delivered by the costimulatory CD28-B7 pathway and the altered production of immunoregulatory cytokines, in particular IL-10, whose production is altered in HIV-1 infection. In this study we investigate IL-10 regulation in T cells and monocytes from HIV⁺ individuals, and its association with CD28-mediated T cell proliferation. IL-10 production as analysed in T cell- and monocyte-depleted peripheral blood mononuclear cells (PBMC), and by intracellular staining at the single-cell level, reveals a defect in IL-10 production by CD4⁺ and CD8⁺ T cells, whereas monocytes constitute the major IL-10-producing cell type. To investigate the impact of IL-10 on immune responsiveness, CD28-mediated proliferative responses in HIV⁺ individuals were correlated with PHA-induced IL-10 production. CD4⁺ T cells expressed CD28, yet exhibited markedly reduced CD28-mediated cell proliferation. This CD28-mediated CD4⁺ T cell proliferation was found to be inversely associated with the levels of PHA-induced IL-10 production and could be restored, at least in part, by anti-IL-10 antibodies. These results suggest that IL-10 production is differentially regulated in T cells and monocytes of HIV⁺ individuals, and that IL-10 may have a role in inducing immune unresponsiveness by modulating the CD28-B7 pathway.     

Cyclin D1和p16、p27在脑胶质瘤中的表达及其与PCNA的相关性

目的 :检测CyclinD1 和p16、p2 7以及PCNA在脑胶质瘤中的表达状况 ,以探讨不同病理类型脑胶质瘤中各自的表达及其相关性。方法 :应用免疫组化S P法 ,检测 12例正常脑组织、5 8例脑胶质瘤组织中CyclinD1 、p16、p2 7及PCNA表达及其特征。结果 :CyclinD1 在由低度恶性胶质瘤向高度恶性胶质瘤转化中阳性表达逐渐增强 (χ2 检验 ,P <0 0 0 5 ,χ2 =5 1 6 7) ;而p16、p2 7阳性表达却是随着胶质瘤恶性程度的升高而降低 (χ2 检验 ,P值均 <0 0 0 5 ,χ2 分别为 15 4 1和 12 81)。CyclinD1 与PCNA呈正相关 ,rs =0 74 5 ;p16和p2 7与PCNA呈负相关 ,rs分别为 - 0 5 6 6和 - 0 6 12。结论 :脑胶质瘤中CyclinD1的表达程度对胶质瘤的细胞增殖活性起促进作用 ,而p16、p2 7的表达则起抑制作用。