Functional interactions between interleukin-4, interleukin-2, and tumor necrosis factor-alpha for lymphokine-activated killer cell generation

The purpose of the present study was to explore the interaction between interleukin-2 (IL-2), interleukin-4 (IL-4), and tumor necrosis factor-alpha (TNF) on the differentiation of human large granular lymphocytes (LGL) into lymphokine-activated killer cells (LAK). The data show that recombinant human IL-4 (100-1,000/ml) was able to induce the differentiation of human LGL into LAK effectors. The levels of the IL-4-induced cytotoxicity are significantly lower than those observed after stimulation of LGL by optimal doses of IL-2. This LAK activity generation by IL-4 was not associated with LGL proliferation. When TNF was added in LGL culture in the presence of suboptimal concentrations of IL-4, the lytic capacity of the activated killer cells was significantly enhanced, suggesting an apparent synergy between these two factors. Most interestingly, our data indicate that exogenous TNF can partially overcome the known inhibitory effect of IL-4 on IL-2-induced LGL differentiation into LAK effectors. These findings suggest a role for TNF in the process of LAK induction.     

The effects of hydrocortisone on in vitro lymphocyte proliferation and interleukin-2 and -4 production in corticosteroid sensitive and resistant subjects

Abstract. Corticosteroids (CS) are potent immunosup-pressive and anti-inflammatory agents which are frequently used to treat a number of conditions such as rheumatoid arthritis (RA), asthma, and renal allograft rejection. Patients taking corticosteroids can be divided into 'steroid-sensitive' (SS) and 'resistant' (SR) groups on clinical and laboratory criteria. Corticosteroid 'resistance' has been extensively documented in asthma and renal allografting. The underlying mechanisms are unknown. Using the inhibition by hydro-cortisone of concanavalin-A induced lymphocyte proliferation in vitro , we have divided rheumatoid arthritis patients (RA) and normal controls (HC) into SS and SR groups. The SS and SR phenotypes were stable over several months in RA and HC subjects. Inhibition of Con-A induced production of interleukin-2 and -4 by corticosteroids in vitro correlated with the in vitro defined SS and SR phenotype. When highly purified T-cells were stimulated via the CD3 and CD28 receptor pathways, corticosteroids did not inhibit cell proliferation in SS and ST subjects. It may be concluded that the SS and SR phenomenon is a stable intrinsic property of the individual which is dependent primarily on the inhibitory effects of corticosteroids on accessory cell function and only secondarily on T-cell function. This is a novel observation for the inhibitory effects of corticosteroids on T-lymphocytes.     

自细胞介素4和受体基因多态性与儿童变应性哮喘的相关分析

[目的]探讨白细胞介素4（IL-4）及受体（IL-4R）基因多态性与儿童变应性哮喘易感性及与血浆总IgE的关系。[方法]采用聚合酶链反应-限制性酶切多态性方法检测IL-4基因启动子区-589位和IL-4Rα亚单位Q576R两位点基因多态性，并观察对血浆总IgE的影响。[结果]研究发现白细胞介素-4基因-589基因多态性与儿童支气管哮喘无相关关系；IL-4受体仅亚单位RR基因型和R576等位基因频率在儿童支气管哮喘与对照组相比有显著性差异（χ^2=22．90，P〈0．001;χ^2=25．30，P〈0．001），且R576与高IgE相关。[结论]表明IL-4Rα亚单位R576是中国汉族哮喘患者的危险因子，且与高IgE相关。     

金边瑞香浸膏对小鼠血清IFN-γ、IL-4、IL-18表达的影响

目的观察金边瑞香（daphne odora var.marginata,DOVM）浸膏对小鼠血清干扰素γ（IFN-γ）、白细胞介素4（IL-4）、白细胞介素18（IL-18）表达的影响。方法选用昆明系小鼠60只,随机分为生理盐水组（对照组）和1、2、4、8、16 g/（kg.d）DOVM浸膏组共6组,每组10只。DOVM浸膏不同浓度组分别灌胃给药0.02 mL/g,1次/d,连续14 d;生理盐水组给予生理盐水灌胃0.02 mL/g,1次/d,连续14 d。常规分离血清后,采用生物素双抗体ELISA夹心法（ABC-ELISA）测定各组小鼠血清IFN-γ、IL-4、IL-18的水平。结果1 g/（kg.d）DOVM浸膏组血清IL-4水平明显高于生理盐水组（P〈0.05）。生理盐水组与DOVM浸膏不同浓度组血清IFN-γ、IL-18水平比较差异均无统计学意义（P均〉0.05）,DOVM浸膏不同浓度组间血清IFN-γ、IL-18水平比较差异也均无统计学意义（P均〉0.05）。结论1 g/（kg.d）DOVM浸膏对小鼠IL-4的表达有一定促进作用。     

体外循环中T淋巴细胞IL-4 IFN-γmRNA的表达变化及意义

目的研究体外循环（CPB）中T淋巴细胞IL-4、IFN—γmRNA的表达变化及意义。方法随机抽取年龄6-12岁先心病惠儿30例，分别于术前24h、CPB开始20min、CPB结束前、术后6h、术后24h抽取静脉血，分离T淋巴细胞．提取RNA，RT—PCR测定IL-4、IFN-γmRNA表达。结果CPB开始20min，T淋巴细胞IL-4mRNA表达明显升高，在CPB结束前达到峰值，术后24h逐渐恢复至术前水平；IFN-γmRNA表达在CPB开始20min下调，CPB结束前达到谷底，术后24h逐渐恢复至术前水平。结论CPB引起T淋巴细胞IL-4．mRNA表达上调、IFN-γmRNA下调，说明CPB可导致Th1／Th2失衡，在CPB创伤、炎性反应中可能起重要作用。     

雷公藤对哮喘的治疗作用及对痰液中嗜酸细胞IL4和IL-5mRNA表达的影响

目的 探讨雷公藤对哮喘的治疗作用及对痰液中嗜酸细胞(EOS)IL-4和IL-5mRNA表达的影响.方法 12例哮喘患者的诱导痰标本,与雷公藤内酯醇(10-7 mol/L)共同培养48小时设为雷公藤组(12例),单独培养48小时设为空白组(12例),健康自愿者痰液为正常对照组.采用斑点分子杂交检测EOS IL-4、IL-5mRNA表达.结果 哮喘患者痰液中EOS浸润密度与正常对照组比较,差异有显著性意义(P<0.01);雷公藤组与空白组EOS IL-4、IL-5mRNA表达水平比较,差异有显著性意义(P<0.01),空白组与正常对照组EOS IL-4、IL-5mRNA表达水平比较,差异有显著性意义(P<0.01);雷公藤组与正常对照组EOS IL-4、IL-5mRNA表达水平比较,差异无显著性意义(P>0.01).结论 IL-4、IL-5mRNA表达增加可能是导致哮喘嗜酸气道炎症的原因,雷公藤内酯醇能抑制IL-4、IL-5mRNA表达,可能为哮喘抗炎治疗的机制之一.     

CD4+CD25+调节性T细胞的研究进展

CD4^＋CD25^＋调节性T细胞（regulatory T cell,Treg）具有维持自身免疫耐受和调节免疫应答的功能,其功能紊乱或数目下降是导致自身免疫性疾病的重要原因之一。近年来,研究发现Foxp3在调控CD4^＋CD25^＋Treg细胞的发育和功能上起着重要作用。本文就CD4^＋CD25^＋Treg细胞的免疫抑制机制、Foxp3在其发育和功能上的作用、IL-2和细胞毒性T淋巴细胞相关抗原4（CTLA-4）等对其产生、维持及活化的作用等方面作一综述。     

哮喘患者诱导痰中嗜酸细胞IL-4和IL-5mRNA表达

目的 :探讨IL - 4、IL - 5在哮喘诱导中痰嗜酸细胞 (EOS)炎症的作用。方法 :斑点分子杂交检测哮喘患者诱导痰中嗜酸细胞IL - 4、IL - 5mRNA表达。结果 :哮喘患者痰液中EOS细胞浸润密度增加 ,IL - 4、IL - 5mRNA表达比正常人明显升高 (p<0 .0 1) ,而正常对照组无明显变化 (p >0 .0 5 )。结论 :IL - 4、IL - 5mRNA表达增加可能在导致哮喘EOS气道炎症的过程中起信号途径作用。     

rhGM-CSF和rhIL-4诱导的髓性白血病细胞刺激自体T细胞增殖与IFN-γ分泌作用

为了研究rhGM-CSF和rhIL-4诱导的髓性白血病细胞刺激自体T细胞的增殖作用和IFN-γ的分泌作用。运用rhGM-CSF和rhIL-4在体外进行CML和AML外周血MNC培养，培养的第7天运用流式细胞术测定CML和AML细胞的CD80，CD86和HLA-DR表达；以诱导的白血病细胞作为刺激细胞，自体T细胞作为反应细胞，在体外进行混合淋巴细胞培养（MLR），测定自体T细胞的增殖情况和IFN-γ的分泌情况。结果显示,rhGM-CSF和rhIl-4明显上调CML细胞HLA-DR，CD80和CD86的表达，并明显上调AML细胞的CD80与CD86表达；诱导后的白血病细胞刺激自体T细胞明显的增殖和促进IFN-γ的分泌（CML组）作用。结论：rhGM-CSF和rhIL-4诱导的CML和AML细胞可能具有向自体T淋巴细胞递抗原的能力。     

白细胞介素-27研究进展

细胞因子介导的免疫反应在许多疾病的发病机制中均发挥着关键性作用。白细胞介素-27（IL-27）是近期新发现的隶属于IL-6/IL-12家族的细胞因子,它通过不同的作用机制参与自身免疫性疾病、炎症及肿瘤等多种疾病的发生、发展及转归。许多研究证明,在缺乏IL-27的免疫疾病中,多种炎症因子高表达,从而产生严重的炎症反应。然而,IL-27还能促进Th1细胞的分化,具有一定的促炎作用。因此,IL-27具有免疫抑制和促炎双重作用。本文主要从IL-27在自身免疫性疾病、感染和肿瘤等疾病中发挥的作用及近期研究进展方面加以阐述。     

Cytokines and Migraine: Increase of IL-5 and IL-4 Plasma Levels

Thirty-two patients suffering from migraine without aura were assessed during the interictal period to evaluate the contribution of cytokines to the pathophysiology of migraine. To this end, plasma levels of IFN-γ, IL-4, IL-5, and IL-10 were measured by enzyme-linked immunosorbent assay (ELlSA) techniques. Plasma levels of both IFN-γ and IL-10 were not increased in the patients and did not differ significantly from healthy controls. Of interest, we observed a strong increase of IL-5 levels in 84.3% as well as increased IL-4 levels in 37.5% of patients with migraine without aura. These results suggest a preferential enhancement of some Th2-type cytokines and may support the growing arguments of an immunoallergic mechanism in the pathophysiology of migraine.     

Breaking the asymptomatic phase of HIV-1 infection

AIDS typically consists of three phases: (1) an acute, infectious mononucleosis-like syndrome followed by (2) a prolonged asymptomatic stage ending in (3) the appearance of frank AIDS. The asymptomatic phase may last for years and its presence suggests a persistent conflagration between the virus and the host's immune response. There is considerable evidence that an immune response develops but the response is ultimately inadequate. From the work of others as well as our own, we have constructed a hypothesis which attempts to explain some aspects of the immune response. We propose that HIV-1 preferentially infects a subset of CD4⁺ lymphocytes which are then either destroyed or altered in their biological functions. Further, we suggest that this subset represents the CD4⁺ TH1 lymphocyte population. By decreasing the quantity of IL-2 and interferon-gamma produced by TH1 lymphocytes, the production of cytokines by TH2 cells is increased. One of the cytokines produced by TH2 lymphocytes is IL-10, a polypeptide with significant inhibitory properties towards lymphocytes. Sera from patients with frank AIDS have significant lymphocyte inhibitory activities some of which operate through IL-10. Thus, a gradual shift to a TH2-type response and release of increasing amounts of inhibitors eventually prevents the host from replacing destroyed cells or mounting new and appropriate immune responses. © 1994 Wiley-Liss, Inc.     

白细胞介素4和白细胞介素10基因多态性与胃癌易感性的关系

目的：分析白细胞介素4(IL-4)rs2070874,白细胞介素10(IL-10)rs1800871、rs1800872基因型及其基因频率在汉族成年胃癌患者与正常对照人群中的分布情况,探讨 IL-4,IL-10基因多态性与胃癌临床易感性的关系。方法病例组胃癌患者84例,正常对照组105例,两组均留取外周静脉血提取 DNA,利用直接测序法对 IL-4 rs2070874,IL-10 rs1800871、rs1800872进行基因型测定,分析各位点多态性与胃癌临床易感性关系。结果 IL-4 rs2070874基因多态性在病例组与对照组等位基因之间、基因型之间的分布差异有统计学意义(P <0.05);IL-10 rs1800871、rs1800872基因多态性在病例组与对照组等位基因之间、基因型之间的分布差异无统计学意义(P >0.05)。结论 IL-4 rs2070874基因多态性与胃癌感染易感性有关,而 IL-10 rs1800871、rs1800872位点基因多态性与胃癌易感性可能不相关。     

Interleukin-4 induces both IgG4 and IgE secretion by peripheral blood B cells

Peripheral blood mononuclear cells (PBMCs) from healthy nonallergic donors were cultured with recombinant interleukin-4 (rIL-4), and the Ig of different isotypes was quantitated in the culture supernatants by radioimmunoassays. Recombinant IL-4 induced IgG4 and IgE secretion in a dose-dependent manner, whereas it had no consistent effect on the secretion of the other isotypes. In the absence of rIL-4, B cells in the PBMC preparations secreted less than 1 ng IgE/ml and a mean of 5 ng IgG4/ml. In the presence of the optimal dose of 100 U rIL-4/ml, PBMCs from five donors secreted a mean +/- SEM of 37 +/- 8 ng IgE/ml and 66 +/- 25 ng IgG4/ml. In kinetic studies, no IgG4 or IgE secretion was detected during the first 5 days of culture, and approximately 50% of the IgG4 and IgE secreted by day 15 was detected in supernatants on day 7. Cycloheximide, actinomycin-D, and mytomycin-C completely inhibited the rIL-4-induced IgG4 and IgE secretion, indicating that de novo protein, RNA, and DNA synthesis was required. As shown by Percoll buoyant density centrifugation, rIL-4 induced B cells in the high-density fraction to secrete IgG4 and IgE, whereas it inhibited spontaneous IgG4 secretion by low-density B cells. Interferon-gamma inhibited IL-4-induced IgG4 and IgE secretion. The data demonstrate that IL-4 induces small, dense, peripheral blood B cells to secrete not only IgE but also IgG4, which parallells the IL-4-induced IgE and IgG1 secretion by murine B cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

肺炎支原体肺炎患儿血清中白细胞介素水平与伴发喘息的相关研究

目的探讨肺炎支原体肺炎患儿血清中白细胞介素4(IL-4)、白细胞介素5(IL-5)、白细胞介素13(IL-13)水平及其与喘息发生的关系。方法收集2013年1~10月123例肺炎支原体肺炎患儿,根据临床表现分为喘息组53例和无喘息组70例,喘息组根据临床病情分为急性期喘息组23例和缓解期喘息组30例,同时收集同期50例无喘息健康儿童血清作对照,采用酶联免疫吸附试验(ELISA)测定血清中IL-4、IL-5、IL-13水平。结果肺炎支原体肺炎患儿血清中IL-4、IL-5、IL-13水平高于健康对照组,喘息组患儿血清中IL-4、IL-5、IL-13水平高于无喘息组患儿,血清IL-4、IL-5、IL-13在急性期喘息组、缓解期喘息组中水平差异具有统计学意义(P0.05)。患儿血清中IL-4、IL-5水平呈正相关(r=0.613,P0.05),其余指标无相关性。结论血清IL-4、IL-5、IL-13在肺炎支原体肺炎伴喘息患儿中水平升高,且伴随着喘息症状的加重水平上升,对肺炎支原体肺炎的治疗有指导意义。     

Comparison of interferon-γ and interleukin-4 production by peripheral blood mononuclear cells and isolated T cells after activation with polyclonal t cell activators

Controversial data have been reported regarding the ability of peripheral blood T cells to secrete interferon-γ (IFN-γ) and interleukin-4 (IL-4) from atopic patients as compared to nonatopic healthy controls. In most of these studies, T cells in peripheral blood mononuclear cell preparations (PBMC) were stimulated with polyclonal T cell activators. Some of these activators are able to activate cells other than T cells in the PBMC preparations which may influence the lymphokine levels in supernatants of PBMC. To evaluate this, we compared the IFN-γ and IL-4 levels in PBMC and isolated T cell preparations after activation with phytohemagglutinin (PHA), Concanavalin A (ConA), anti-CD3 plus phorbol myristate acetate (PMA), or ionomycin plus PMA. The IFN-γ and IL-4 levels in the supernatants were calculated based on the percent T cells in the preparations. Whereas all activators induced significant IFN-γ secretion, only ionomycin plus PMA stimulation induced large IL-4 secretion. In virtually all cases, the IFN-γ levels calculated on a per T cell basis differed for PBMC versus isolated T cells. Whereas in some donors the IFN-γ levels were higher in PBMC preparations than in T cells, in others it was the opposite. Similarly, in about one half of both normal and atopic donors tested, the IL-4 levels of activated PBMC were 2- to 7-fold lower than levels in isolated T cells. The data suggest that non-T cells have a significant effect on the IFN-γ and IL-4 levels in supernatants of polyclonally activated PBMC. This indicates that isolated T cells rather than PBMC should be analyzed for determining possible differences in the ability of T cells from patients or normals to secrete lymphokines. © 1994 Wiley-Liss, Inc.     

SLE患者T细胞亚群功能紊乱与Th1、Th2细胞因子偏移的研究

目的 :探讨系统性红斑狼疮 (SLE)患者细胞因子表达异常与细胞免疫功能紊乱的机制。方法 :用流式细胞仪根据直接免疫荧光法分别测定病例组与对照组T细胞表面标志CD3 ,CD4,CD8的表达情况。用微量反应板根据酶联免疫吸附测定法分别测定病例组与对照组血清IL - 2及IL - 6水平。结果 :SLE患者CD3 + CD4+ 细胞较正常对照组明显降低 (P <0 0 1) ,CD3 + CD8+ 细胞较正常对照组明显增加 (P <0 0 1) ,CD4+ T/CD8+ T细胞比例倒置 ;血清IL - 2水平较正常对照组明显降低 (P <0 0 1) ,而血清IL - 6水平较正常对照组明显增高 (P <0 0 5 )。结论 :SLE患者体内细胞免疫功能紊乱是介导免疫调节紊乱的主要因素 ,CD4+ T/CD8+ T细胞比例倒置 ,而CD4+ T细胞水平明显降低 ,其Th1,Th2细胞功能也表现明显偏移 ,以Th2细胞亢进为主 ,产生大量Th2细胞因子 ,介导免疫调节反应 ,致B淋巴细胞活跃产生大量自身抗体及免疫球蛋白。同时 ,CD8+ T细胞功能亢进 ,CTL细胞参与机体组织损伤 ,进一步导致免疫紊乱及免疫病理损伤加重     

白细胞介素-4、白细胞介素-8、白细胞介素-9在支气管哮喘患儿血清中的表达及临床意义

目的 观察白细胞介素(IL)-4、IL-8、IL-9在支气管哮喘患儿血清中的表达,并探讨其临床意义.方法 选取支气管哮喘急性发作期、临床缓解期患儿各43例,分别设为发作组和缓解组,另选取同期体检健康儿童37例作为对照组,检测所有儿童的血清IL-4、IL-8、IL-9水平.结果 IL-4、IL-8、IL-9在对照组、缓解组、发作组儿童血清中的表达水平均呈递增趋势,组间比较均有显著差异(P＜0.01).结论 血清IL-4、IL-8、IL-9水平与支气管哮喘的发生、发展过程密切相关,临床可作为支气管哮喘病情进展的参考指标.