富硒益生菌对猪细胞免疫的调节作用及其机理研究
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摘要
硒是人和动物必需的微量元素之一,具有调节机体代谢、提高机体免疫力和抗病力、影响人和动物的生殖机能、抗肿瘤、抗自由基、延缓衰老和拮抗有毒元素等多种重要的生物学功能,所以日粮补硒现已是许多国家养殖业采取的常规措施。硒在体内以硒代半胱胺酸的形式掺入到各种硒蛋白中,通过后者发挥其生物学功能。益生菌具有维持肠道菌群平衡、防治胃肠道疾病,产生多种酶类、合成多种营养物质、促进生长,增强机体免疫机能等生物学功能,目前广泛作为饲料添加剂应用。当前广泛使用的补硒方法是添加无机硒——亚硒酸钠,但由于亚硒酸钠利用率低、毒性大,其本身具有过氧化作用,而且对环境会造成潜在的污染,因此一些国家已经限制使用亚硒酸钠作为硒的营养补充剂。富硒益生菌是本实验室研制的饲料添加剂产品,能同时发挥有机硒和益生菌的双重生物学功能,已获国家发明专利。前人的研究表明,有机硒(如富硒益生菌,主要含硒蛋氨酸)的毒性小、生物利用率高。本文研究了日粮添加富硒益生菌对仔猪生产性能、免疫功能、硒的吸收转化、抗氧化能力和淋巴细胞中主要硒酶mRNA表达的影响,并在细胞和分子水平上探讨其主要的有机硒成分(硒蛋氨酸,Se-Met)对细胞免疫的作用机理,为富硒益生菌在生猪养殖生产上的广泛应用提供理论依据。
试验1.猪GPx1、GPx4及TR1mRNA表达水平Real-time PCR检测方法的建立
根据已公布猪的β-actin、GPx1、GPx4和TR1基因的mRNA序列,应用生物软件辅助设计并合成4对特异性引物；以Oligo dT为引物,对从猪脾脏中抽提的总RNA进行反转录,合成第一链cDNA;以cDNA为模板,分别进行4个目的基因片段的PCR扩增；胶回收PCR产物,将其克隆到pMD18-T载体上并测序；对抽提的重组质粒进行拷贝数测定,以10倍梯度稀释的质粒作为标准模板进行PCR扩增,同时对荧光定量PCR反应的引物浓度和退火温度进行优化。结果,4对引物分别扩增出一条目的带,且大小与预期相符合；荧光定量PCR反应的最佳引物浓度是10μmo/L加入0.4μl,最佳退火温度为60℃；各荧光定量PCR产物熔解曲线均显示单一峰,表明产物单一；各目的基因的标准曲线的R2均达到0.99以上,符合要求。结果表明,本试验成功地建立了检测猪GPx1、GPx4和TR1mRNA水平的荧光定量PCR方法。
试验2.日粮添加富硒益生菌对仔猪生长性能和免疫功能的影响
48头健康断奶仔猪(杜×长×大),随机均分为对照组、益生菌组、富硒酵母组、亚硒酸钠组和富硒益生菌组。对照组(C)饲喂基础日粮；益生菌组(P)日粮中添加益生菌；其余2组日粮中分别添加富硒益生菌(SP)和亚硒酸钠(SS),其剂量以硒计均为0.3mg/kg饲料。整个试验期为42d。在试验0d和42d分别测定生产性能相关指标；于试验的第0、14、28和42d,采集血液样品,用于分析血清猪瘟抗体水平、IL-2和TNF-α浓度。在试验的第42d,每组随机选择3头仔猪,采集血样和脾脏,用于分析T淋巴细胞转化情况。结果,日粮中添加P、SS和SP均可显著改善饲料的报酬率,提高仔猪的平均末重、平均日增重和料重比(P<0.05)；在添饲后的第42d,P组、SP组和SS组的血清猪瘟抗体水平均显著高于对照组(P<0.05)；在添饲后的第42d,P组、SS组和SP组仔猪外周血淋巴细胞和脾脏淋巴细胞的T细胞增殖能力显著高于对照组(P<0.05),并且SP组仔猪的淋巴细胞T细胞增殖能力显著高于其他各组(P<0.05)；在第42d,SP组和SS组和P组的IL-2和TNF-α浓度均显著高于对照组(P<0.05),并且SP组仔猪的细胞因子水平有高于其他各组的趋势(P>0.05)；以上结果表明,富硒益生菌能提高仔猪的生产性能和提高仔猪的免疫功能,并且其提高仔猪细胞免疫的效果优于亚硒酸钠。
试验3.日粮添加富硒益生菌对仔猪硒沉积和抗氧化能力的影响
试验设计同试验2。于试验的第0、14、28和42d,采集血液样品,用于分析血硒含量、红细胞GPx1活性、血浆GPx3活性和血浆MDA含量。于试验的第42d,每组随机选择3头仔猪,采集各组织样品,用于分析组织硒含量。结果,日粮中添加SP组的仔猪全血Se含量显著高于SS组(P<0.05),并且两组均显著高于对照组(P<0.05),而P组与对照组的全血硒含量差异均不显著(P>0.05)。在第42d,SP组和SS组的肝脏、肾脏、肌肉和脾脏硒含量均显著高于对照组和P组(P<0.05),并且SP组与其他各组相比均差异显著(P<0.05),而P组与对照组的肝脏、肾脏、肌肉和脾脏硒含量差异均不显著(P>0.05)；在日粮中添加SP和SS组可以显著提高仔猪红细胞GPx1活性(P<0.05),且SP组的最高,而P组与对照组的红细胞GPx1活性差异均不显著(P>0.05)；在整个试验期间,SP组和SS组的血浆GPx3活性均显著高于对照组和P组(P<0.05)；在第14、28和42d,SP组和SS组的血浆MDA含量均显著低于对照组和P组(P<0.05),且SP组的血浆MDA含量均显著低于SS组(P<0.05)。以上结果表明,与亚硒酸钠相比,富硒益生菌在提高仔猪血硒和组织硒含量、机体抗氧化能力和降低血浆MDA含量方面更为优越。
试验4.日粮添加富硒益生菌对仔猪外周血淋巴细胞主要硒酶mRNA表达的影响
试验设计同试验2。于试验的第0、14、28和42d,采集血液样品,用于分析外周血淋巴细胞中GPx1、GPx4和TR1mRNA水平。结果,在第14、28和42d,与对照组比,SS和SP组的仔猪外周血淋巴细胞GPx1和TR1mRNA水平均显著升高(P<0.05),且SP组仔猪外周血GPxl mRNA水平显著高于其他组(P<0.05),而所有硒处理组的淋巴细胞GPx4mRNA水平无显著变化；以上结果表明,硒对不同的硒蛋白的调控并不相同,日粮中硒水平的改变对淋巴细胞GPx1mRNA的表达影响最大,对TR1mRNA的表达影响次之,而对于GPx4mRNA的表达几乎没有影响。而且富硒益生菌促进淋巴细胞GPx1mRNA表达的效果更好。
试验5.硒对不同丝裂源介导的猪脾脏淋巴细胞T细胞活化的影响
来自健康仔猪的原代脾脏淋巴细胞用0(对照)、0.5、1、2和4μmo/L的亚硒酸钠(Na2SeO3)(?)育,并使用不同丝裂源刺激培养48h。结果,硒显著的促进了刀豆蛋白A (ConA)和T细胞受体(TCR)介导的T淋巴细胞增殖和IL-2的产生,但是对植物血凝素(PHA)介导的T淋巴细胞活化没有影响,使用流式细胞术测定T细胞的增殖情况,进一步证实了这一结果；在不受刺激、TCR、ConA或PHA刺激的淋巴细胞中,添加硒的各组GPx1mRNA和TR1mRNA水平、细胞内还原型GSH浓度和GPx活性均显著提高(P<0.05)。这些结果表明硒改善了不同丝裂源刺激的淋巴细胞的氧化还原状态,但是只有TCR和ConA介导的淋巴细胞活化受到了影响。而作为一种单纯的抗氧化剂,NAC显著的促进了TCR或ConA介导的淋巴细胞活化,但是对PHA刺激淋巴细胞没有影响,进一步证明了PHA介导的淋巴细胞增殖对于氧化还原状态的改变并不敏感。以上结果表明,硒对不同丝裂源介导的淋巴细胞活化的调控是有差异的；而导致这一差异的主要原因是因为TCR、ConA以及PHA介导的淋巴细胞对于氧化还原状态存在不同的敏感性。
试验6.不同形式和浓度的硒对原代脾脏淋巴细胞T细胞增殖的调控
来自健康仔猪的的原代脾脏淋巴细胞用使用5μg/ml的ConA刺激,并同时加入0(对照)和各种浓度的(以硒计)硒蛋氨酸(Se-Met)或亚硒酸钠(Na2SeO3)孵育培养48h。结果,0.5-32μmol/L的Se-Met处理组的ConA介导的T细胞增殖显著高于对照组(P<0.05),而Na2SeO3处理组的淋巴细胞增殖在2μmol/L时达到最大值,之后随着浓度的增大而降低,呈剂量依赖模式,并且在8μmol/L及更高浓度会抑制T淋巴细胞的增殖；添加0.5-4μmol/L的Se-Met或Na2SeO3的细胞内还原型GSH浓度均显著高于对照组(P<0.05),但是Na2SeO3添加浓度大于2μmol/L时,会使得GSH浓度与最高值相比下降。添加Se-Met或Na2SeO3的细胞内GPx1mRNA水平均显著升高(P<0.05),而两种形式的硒处理细胞的GPx4mRNA水平无显著变化(P>0.05)；添力口0.5-4μmol/L的Se-Met或Na2SeO3可以显著提高细胞内GPxl活性(P<0.05),而且4μmol/L的Se-Met处理组的GPx1活性水平在所有Se处理组中最高(P<0.05；添加GPx1的抑制剂巯基琥珀酸(MS)可以使硒促进淋巴细胞增殖的作用消失,并且显著抑制淋巴细胞的增殖。综上所述,不同形式和浓度的硒对ConA介导的原代培养猪脾脏淋巴细胞增殖的调控是有差异的,GPx1可能是其中的关键酶。
Selenium (Se) is an essential trace element for animals and humans. Se has many biological functions including regulating metabolism, enhancing the antioxidative ability, immune function, reproductive performance, and reducing the risk of diabetes, cardiovascular disease, certain types of cancer and resisting to detoxification from some heavy metals. In many countries, supplementation of selenium in animal diet is a routine step on animal husbandry. Se is incorporated into selenoproteins as selenocysteine and exerts its biological functions. Probiotics, which are reported to exert a myriad of beneficial effects including balance of colonic microbiota, prevention and treatment of certain diarrhoeal diseases, improvement of growth performance, enhancement of immune response, reduction of serum cholesterol and inhibition of cancer, are diffusely served as feedstuff additive in stockbreeding. Adding sodium selenite as inorganic selenium in animal diet has been set limit in some countries because inorganic selenium has disadvantages of lower bioavailability, higher toxicity and potential environmental pollution. Precious studies have suggested that organic forms of Se (e.g., Se-enriched yeast, which contains selenomethionine) are less toxic than inorganic forms of Se such as sodium selenite, and the bioavailability of organic Se is relatively high. The preparation of Se-enriched Probiotics was made in our lab and used for nutritional supplementation in diets, which can exert dual effects of organic Se and probiotics at the same time. Invention patent for the preparation was awarded by State Intellectual Property Office of The P.R.C. The present study was conducted to evaluate the effects of supplementary Se-enriched probiotics on transform of Se, immune function, antioxidative ability and major selenoproteins mRNA levels of lymphocytes in piglets, and to explore its mechanism at the cellular and molecular levels, so that to provide a theoretical basis for application of Se-enriched probiotics in pig husbandry.
Experiment1. Development of the method for determination of GPx1, GPx4, and TR1mRNA levels in pig by real-time PCR
According to the published mRNA sequences of gene of P-actin, GPx1, GPx4, and TR1, four pairs of specific primers were designed by biological software and synthesized. Oligo dTs were used as primer and first strand cDNAs were synthesised from total RNA, which was isolated from bovine hepatocytes. Using the synthesised cDNAs as template, four target fragments were amplified by polymerase chain reaction (PCR), respectively. The PCR products were electrophoresed on2%agarose gels and extracted. The extracted PCR products were cloned into pMD18-T Vector and sequenced. The copies of extracted plasmids were measured and serially diluted by10-folds. The diluted plasmids were used as standard templates and real-time PCRs were performed. In addition, the contents and annealing temperatures of four pairs of specific primers were optimized, respectively. The results showed that one target band was amplified for each specific primer pair and consistent with the fact. The optimal contents and annealing temperatures of four primer pairs were10μmol/L0.4μL and60℃, respectively. All the R2of four standard curve for gene of β-actin, GPx1, GPx4, and TR1were higher than0.99. The melting curve analysis showed only one peak for each PCR product. These results indicate that the method for determination GPx1, GPx4and D1mRNA levels in pig by real-time PCR is successfully developed.
Experiment2. Effect of supplementary selenium-enriched probiotics on growth performance and immune function in piglets
48health piglets were divided into four groups in a randomized complete block design, of which3were assigned for test groups, and one served as control. The control group(C) received a basal diet. Both selenium-enriched probiotics (SP) and sodium selenite (SS) were added into basal diet at0.3mg/kg of Se to make two experiment diets. Probiotics was added into basal diet to make probiotics group (P). Whole feeding experiment lasted for42days. Blood samples were collected for analysis of serum IL-2and TNF-a concentrations on d0,14,28and42. On the d14and42of the experiment, the serum antibody level of swine fever in3test groups were significantly higher than the control group respectively (P <0.05); The T cell transformation of pig peripheral blood mononuclear cell (PBMC) were significantly higher in The SP, SS and P group than did the control group (P<0.05), and the SP group were significangly higher than the SS group; The serum concentrations of IL-2and TNF-a in3test groups were markedly higher than the control group on d42(P<0.05); The results testified that there is a better effect of supplementation SP than those of supplementation SS or probiotics in boosts immune responses.
Experiment3. Effect of supplementary selenium-enriched probiotics on absorption and transform of selenium and antioxidative ability of piglets
Experiment design is the same as the experiment1. Whole feeding experiment lasted for42days. Blood samples were collected for analysis of whole blood selenium (Se) concentrations, erythrocyte glutathione peroxidase activity (RBC GPx), plasma GPx3activity and plasma Malondialdehyde (MDA) concentrations on d0,14,28and42. The Se-Pro group and the Na2SeO3group had significantly higher Se concentrations in whole blood than did the control group and the Pro group (P<0.05) d14,28and42, respectively, and the Se concentrations in whole blood of SP group were significantly higher than SS group; Se concentrations in liver, kidney, muscle and spleen in the SP group and the Na2SeO3group were significantly higher than the control group and the Pro group (P <0.05), and the Se concentrations in the SP group were significantly higher than SS group(P<0.05); The Se-Pro group and the Na2SeO3group had significantly higher RBC GPx activities than did the control group and the Pro group (P<0.05) on d14,28and42, respectively, while there were no differences between Pro group and control group (P>0.05). The plasma GPx3activities were not different between the treatment groups and the control group in the whole experiment period (P>0.05). The plasma MDA concentrations in Se-Pro group and Na2SeO3group were significantly lower than that in control group and Pro group (P<0.05) on d14,28and42, respectively. Furthermore, the plasma MDA concentrations in SP group were significantly lower than that in Na2SeO3group (P<0.05) on d14,28and42, respectively. The results suggest that SP is more effective than Na2SeO3for increasing Se concentrations in whole blood and tissue, antioxidative ability and decreasing plasma MDA concentrations in piglets.
Experiment4. Effect of supplementary selenium-enriched probiotics on GPxl, GPx4and TR1mRNA levels in PBMC of piglets
Experiment design is the same as the experiment1. Whole feeding experiment lasted for42days. Blood samples were collected for analysis of GPxl, GPx4and TR1mRNA levels on d0,14,28and42. The Se-Pro group and the Na2SeO3group had significantly higher GPxl and TR1mRNA levels than did the control group and the Pro group in the whole experiment period (P<0.05), while there were no differences between Pro group and control group (P>0.05). But the GPx4mRNA levels were not different between the Se-treatment groups and the control group in the whole experiment period (P>0.05). The results suggest that regulation of GPx1, TR1and GPx4mRNA level by Se are different, Se is more effective in improved GPx1mRNA levels than TR1and GPx4mRNA levels, and the GPx4mRNA levels were not affected by Se status.
Experiment5. Regulation of different mitogens induced T-cell activation by selenium in primary cultured pig splenocytes
In this study, the effects of Se on T-cell proliferation and IL-2production were studied in primary porcine splenocytes. Splenocytes were treated with different mitogens in the presence of0.5-4μmol/L sodium selenite. Se significantly promoted T-cell receptor (TCR) or concanavalin A (ConA)-induced T-cell proliferation and IL-2production but failed to regulate T-cell response to phytohemagglutinin (PHA). In addition, Se significantly increased the levels of cytosolic glutathione peroxidase (GPx1) and thioredoxin reductase1(TR1) mRNA, the activity of GPx1and the concentration of reduced glutathione (GSH) in the unstimulated, or activated splenocytes.These results indicated that Se improved the redox status in all splenocytes, including unstimulated, TCR, ConA and PHA-stimulated, but only TCR and ConA-induced T-cell activation was affected by the redox status. N-acetylcysteine (NAC), a pharmacological antioxidant, increased T-cell proliferation and IL-2production by TCR and ConA stimulated splenocytes but had no effect on the response to PHA in primary porcine splenocytes confirming that PHA-induced T-cell activation is insensitive to the redox status. We conclude that Se promotes GPx1and TR1expression and increases antioxidative capacity in porcine splenocytes, which enhances TCR or ConA-induced T-cell activation but not PHA-induced T-cell activation. The different susceptibilities to Se between the TCR, ConA and PHA-induced T-cell activation may help to explain the controversy in the literature over whether or not Se boosts immune responses.
Experiment6. Effects of different forms and concentrations of selenium on ConA induced T-cell proliferation in primary cultured pig splenocytes
Primary cultured pig splenocytes were incubated with0(control) and vary concentrations of Se as DL-selenomethionine (Se-Met), or sodium selenite (Na2SeO3) for48h in the presence of ConA. Compared to controls, significantly higher T-cell proliferation was observed at0.5-32μmol/L Se-Met, Significant increases of T-cell proliferation were obtained in Na2SeO3treated splenocytes at0.5-4μmol/L, with maximal effects at2μmol/L, and inhibited T-cell proliferation in a dose-dependent manner at8-32μmol/L. Intracellular reduced glutathione (GSH) contents and GPx activity in all Se-treated splenocytes were significantly higher than controls. An increases of GPx1mRNA level were obtained in all Se-treated splenocytes, but GPx4mRNA level was not affected by Se-treatment. And the MS, the inhibitor of the GPx1, significantly inhibited the proliferation improved by Se. We conclude that (i) regulation of ConA induced T-cell proliferation by different Se forms are different in primary cultured pig splenocytes, and GPxl maybe the key enzyme.
试验1.猪GPx1、GPx4及TR1mRNA表达水平Real-time PCR检测方法的建立
根据已公布猪的β-actin、GPx1、GPx4和TR1基因的mRNA序列,应用生物软件辅助设计并合成4对特异性引物；以Oligo dT为引物,对从猪脾脏中抽提的总RNA进行反转录,合成第一链cDNA;以cDNA为模板,分别进行4个目的基因片段的PCR扩增；胶回收PCR产物,将其克隆到pMD18-T载体上并测序；对抽提的重组质粒进行拷贝数测定,以10倍梯度稀释的质粒作为标准模板进行PCR扩增,同时对荧光定量PCR反应的引物浓度和退火温度进行优化。结果,4对引物分别扩增出一条目的带,且大小与预期相符合；荧光定量PCR反应的最佳引物浓度是10μmo/L加入0.4μl,最佳退火温度为60℃；各荧光定量PCR产物熔解曲线均显示单一峰,表明产物单一；各目的基因的标准曲线的R2均达到0.99以上,符合要求。结果表明,本试验成功地建立了检测猪GPx1、GPx4和TR1mRNA水平的荧光定量PCR方法。
试验2.日粮添加富硒益生菌对仔猪生长性能和免疫功能的影响
48头健康断奶仔猪(杜×长×大),随机均分为对照组、益生菌组、富硒酵母组、亚硒酸钠组和富硒益生菌组。对照组(C)饲喂基础日粮；益生菌组(P)日粮中添加益生菌；其余2组日粮中分别添加富硒益生菌(SP)和亚硒酸钠(SS),其剂量以硒计均为0.3mg/kg饲料。整个试验期为42d。在试验0d和42d分别测定生产性能相关指标；于试验的第0、14、28和42d,采集血液样品,用于分析血清猪瘟抗体水平、IL-2和TNF-α浓度。在试验的第42d,每组随机选择3头仔猪,采集血样和脾脏,用于分析T淋巴细胞转化情况。结果,日粮中添加P、SS和SP均可显著改善饲料的报酬率,提高仔猪的平均末重、平均日增重和料重比(P<0.05)；在添饲后的第42d,P组、SP组和SS组的血清猪瘟抗体水平均显著高于对照组(P<0.05)；在添饲后的第42d,P组、SS组和SP组仔猪外周血淋巴细胞和脾脏淋巴细胞的T细胞增殖能力显著高于对照组(P<0.05),并且SP组仔猪的淋巴细胞T细胞增殖能力显著高于其他各组(P<0.05)；在第42d,SP组和SS组和P组的IL-2和TNF-α浓度均显著高于对照组(P<0.05),并且SP组仔猪的细胞因子水平有高于其他各组的趋势(P>0.05)；以上结果表明,富硒益生菌能提高仔猪的生产性能和提高仔猪的免疫功能,并且其提高仔猪细胞免疫的效果优于亚硒酸钠。
试验3.日粮添加富硒益生菌对仔猪硒沉积和抗氧化能力的影响
试验设计同试验2。于试验的第0、14、28和42d,采集血液样品,用于分析血硒含量、红细胞GPx1活性、血浆GPx3活性和血浆MDA含量。于试验的第42d,每组随机选择3头仔猪,采集各组织样品,用于分析组织硒含量。结果,日粮中添加SP组的仔猪全血Se含量显著高于SS组(P<0.05),并且两组均显著高于对照组(P<0.05),而P组与对照组的全血硒含量差异均不显著(P>0.05)。在第42d,SP组和SS组的肝脏、肾脏、肌肉和脾脏硒含量均显著高于对照组和P组(P<0.05),并且SP组与其他各组相比均差异显著(P<0.05),而P组与对照组的肝脏、肾脏、肌肉和脾脏硒含量差异均不显著(P>0.05)；在日粮中添加SP和SS组可以显著提高仔猪红细胞GPx1活性(P<0.05),且SP组的最高,而P组与对照组的红细胞GPx1活性差异均不显著(P>0.05)；在整个试验期间,SP组和SS组的血浆GPx3活性均显著高于对照组和P组(P<0.05)；在第14、28和42d,SP组和SS组的血浆MDA含量均显著低于对照组和P组(P<0.05),且SP组的血浆MDA含量均显著低于SS组(P<0.05)。以上结果表明,与亚硒酸钠相比,富硒益生菌在提高仔猪血硒和组织硒含量、机体抗氧化能力和降低血浆MDA含量方面更为优越。
试验4.日粮添加富硒益生菌对仔猪外周血淋巴细胞主要硒酶mRNA表达的影响
试验设计同试验2。于试验的第0、14、28和42d,采集血液样品,用于分析外周血淋巴细胞中GPx1、GPx4和TR1mRNA水平。结果,在第14、28和42d,与对照组比,SS和SP组的仔猪外周血淋巴细胞GPx1和TR1mRNA水平均显著升高(P<0.05),且SP组仔猪外周血GPxl mRNA水平显著高于其他组(P<0.05),而所有硒处理组的淋巴细胞GPx4mRNA水平无显著变化；以上结果表明,硒对不同的硒蛋白的调控并不相同,日粮中硒水平的改变对淋巴细胞GPx1mRNA的表达影响最大,对TR1mRNA的表达影响次之,而对于GPx4mRNA的表达几乎没有影响。而且富硒益生菌促进淋巴细胞GPx1mRNA表达的效果更好。
试验5.硒对不同丝裂源介导的猪脾脏淋巴细胞T细胞活化的影响
来自健康仔猪的原代脾脏淋巴细胞用0(对照)、0.5、1、2和4μmo/L的亚硒酸钠(Na2SeO3)(?)育,并使用不同丝裂源刺激培养48h。结果,硒显著的促进了刀豆蛋白A (ConA)和T细胞受体(TCR)介导的T淋巴细胞增殖和IL-2的产生,但是对植物血凝素(PHA)介导的T淋巴细胞活化没有影响,使用流式细胞术测定T细胞的增殖情况,进一步证实了这一结果；在不受刺激、TCR、ConA或PHA刺激的淋巴细胞中,添加硒的各组GPx1mRNA和TR1mRNA水平、细胞内还原型GSH浓度和GPx活性均显著提高(P<0.05)。这些结果表明硒改善了不同丝裂源刺激的淋巴细胞的氧化还原状态,但是只有TCR和ConA介导的淋巴细胞活化受到了影响。而作为一种单纯的抗氧化剂,NAC显著的促进了TCR或ConA介导的淋巴细胞活化,但是对PHA刺激淋巴细胞没有影响,进一步证明了PHA介导的淋巴细胞增殖对于氧化还原状态的改变并不敏感。以上结果表明,硒对不同丝裂源介导的淋巴细胞活化的调控是有差异的；而导致这一差异的主要原因是因为TCR、ConA以及PHA介导的淋巴细胞对于氧化还原状态存在不同的敏感性。
试验6.不同形式和浓度的硒对原代脾脏淋巴细胞T细胞增殖的调控
来自健康仔猪的的原代脾脏淋巴细胞用使用5μg/ml的ConA刺激,并同时加入0(对照)和各种浓度的(以硒计)硒蛋氨酸(Se-Met)或亚硒酸钠(Na2SeO3)孵育培养48h。结果,0.5-32μmol/L的Se-Met处理组的ConA介导的T细胞增殖显著高于对照组(P<0.05),而Na2SeO3处理组的淋巴细胞增殖在2μmol/L时达到最大值,之后随着浓度的增大而降低,呈剂量依赖模式,并且在8μmol/L及更高浓度会抑制T淋巴细胞的增殖；添加0.5-4μmol/L的Se-Met或Na2SeO3的细胞内还原型GSH浓度均显著高于对照组(P<0.05),但是Na2SeO3添加浓度大于2μmol/L时,会使得GSH浓度与最高值相比下降。添加Se-Met或Na2SeO3的细胞内GPx1mRNA水平均显著升高(P<0.05),而两种形式的硒处理细胞的GPx4mRNA水平无显著变化(P>0.05)；添力口0.5-4μmol/L的Se-Met或Na2SeO3可以显著提高细胞内GPxl活性(P<0.05),而且4μmol/L的Se-Met处理组的GPx1活性水平在所有Se处理组中最高(P<0.05；添加GPx1的抑制剂巯基琥珀酸(MS)可以使硒促进淋巴细胞增殖的作用消失,并且显著抑制淋巴细胞的增殖。综上所述,不同形式和浓度的硒对ConA介导的原代培养猪脾脏淋巴细胞增殖的调控是有差异的,GPx1可能是其中的关键酶。
Selenium (Se) is an essential trace element for animals and humans. Se has many biological functions including regulating metabolism, enhancing the antioxidative ability, immune function, reproductive performance, and reducing the risk of diabetes, cardiovascular disease, certain types of cancer and resisting to detoxification from some heavy metals. In many countries, supplementation of selenium in animal diet is a routine step on animal husbandry. Se is incorporated into selenoproteins as selenocysteine and exerts its biological functions. Probiotics, which are reported to exert a myriad of beneficial effects including balance of colonic microbiota, prevention and treatment of certain diarrhoeal diseases, improvement of growth performance, enhancement of immune response, reduction of serum cholesterol and inhibition of cancer, are diffusely served as feedstuff additive in stockbreeding. Adding sodium selenite as inorganic selenium in animal diet has been set limit in some countries because inorganic selenium has disadvantages of lower bioavailability, higher toxicity and potential environmental pollution. Precious studies have suggested that organic forms of Se (e.g., Se-enriched yeast, which contains selenomethionine) are less toxic than inorganic forms of Se such as sodium selenite, and the bioavailability of organic Se is relatively high. The preparation of Se-enriched Probiotics was made in our lab and used for nutritional supplementation in diets, which can exert dual effects of organic Se and probiotics at the same time. Invention patent for the preparation was awarded by State Intellectual Property Office of The P.R.C. The present study was conducted to evaluate the effects of supplementary Se-enriched probiotics on transform of Se, immune function, antioxidative ability and major selenoproteins mRNA levels of lymphocytes in piglets, and to explore its mechanism at the cellular and molecular levels, so that to provide a theoretical basis for application of Se-enriched probiotics in pig husbandry.
Experiment1. Development of the method for determination of GPx1, GPx4, and TR1mRNA levels in pig by real-time PCR
According to the published mRNA sequences of gene of P-actin, GPx1, GPx4, and TR1, four pairs of specific primers were designed by biological software and synthesized. Oligo dTs were used as primer and first strand cDNAs were synthesised from total RNA, which was isolated from bovine hepatocytes. Using the synthesised cDNAs as template, four target fragments were amplified by polymerase chain reaction (PCR), respectively. The PCR products were electrophoresed on2%agarose gels and extracted. The extracted PCR products were cloned into pMD18-T Vector and sequenced. The copies of extracted plasmids were measured and serially diluted by10-folds. The diluted plasmids were used as standard templates and real-time PCRs were performed. In addition, the contents and annealing temperatures of four pairs of specific primers were optimized, respectively. The results showed that one target band was amplified for each specific primer pair and consistent with the fact. The optimal contents and annealing temperatures of four primer pairs were10μmol/L0.4μL and60℃, respectively. All the R2of four standard curve for gene of β-actin, GPx1, GPx4, and TR1were higher than0.99. The melting curve analysis showed only one peak for each PCR product. These results indicate that the method for determination GPx1, GPx4and D1mRNA levels in pig by real-time PCR is successfully developed.
Experiment2. Effect of supplementary selenium-enriched probiotics on growth performance and immune function in piglets
48health piglets were divided into four groups in a randomized complete block design, of which3were assigned for test groups, and one served as control. The control group(C) received a basal diet. Both selenium-enriched probiotics (SP) and sodium selenite (SS) were added into basal diet at0.3mg/kg of Se to make two experiment diets. Probiotics was added into basal diet to make probiotics group (P). Whole feeding experiment lasted for42days. Blood samples were collected for analysis of serum IL-2and TNF-a concentrations on d0,14,28and42. On the d14and42of the experiment, the serum antibody level of swine fever in3test groups were significantly higher than the control group respectively (P <0.05); The T cell transformation of pig peripheral blood mononuclear cell (PBMC) were significantly higher in The SP, SS and P group than did the control group (P<0.05), and the SP group were significangly higher than the SS group; The serum concentrations of IL-2and TNF-a in3test groups were markedly higher than the control group on d42(P<0.05); The results testified that there is a better effect of supplementation SP than those of supplementation SS or probiotics in boosts immune responses.
Experiment3. Effect of supplementary selenium-enriched probiotics on absorption and transform of selenium and antioxidative ability of piglets
Experiment design is the same as the experiment1. Whole feeding experiment lasted for42days. Blood samples were collected for analysis of whole blood selenium (Se) concentrations, erythrocyte glutathione peroxidase activity (RBC GPx), plasma GPx3activity and plasma Malondialdehyde (MDA) concentrations on d0,14,28and42. The Se-Pro group and the Na2SeO3group had significantly higher Se concentrations in whole blood than did the control group and the Pro group (P<0.05) d14,28and42, respectively, and the Se concentrations in whole blood of SP group were significantly higher than SS group; Se concentrations in liver, kidney, muscle and spleen in the SP group and the Na2SeO3group were significantly higher than the control group and the Pro group (P <0.05), and the Se concentrations in the SP group were significantly higher than SS group(P<0.05); The Se-Pro group and the Na2SeO3group had significantly higher RBC GPx activities than did the control group and the Pro group (P<0.05) on d14,28and42, respectively, while there were no differences between Pro group and control group (P>0.05). The plasma GPx3activities were not different between the treatment groups and the control group in the whole experiment period (P>0.05). The plasma MDA concentrations in Se-Pro group and Na2SeO3group were significantly lower than that in control group and Pro group (P<0.05) on d14,28and42, respectively. Furthermore, the plasma MDA concentrations in SP group were significantly lower than that in Na2SeO3group (P<0.05) on d14,28and42, respectively. The results suggest that SP is more effective than Na2SeO3for increasing Se concentrations in whole blood and tissue, antioxidative ability and decreasing plasma MDA concentrations in piglets.
Experiment4. Effect of supplementary selenium-enriched probiotics on GPxl, GPx4and TR1mRNA levels in PBMC of piglets
Experiment design is the same as the experiment1. Whole feeding experiment lasted for42days. Blood samples were collected for analysis of GPxl, GPx4and TR1mRNA levels on d0,14,28and42. The Se-Pro group and the Na2SeO3group had significantly higher GPxl and TR1mRNA levels than did the control group and the Pro group in the whole experiment period (P<0.05), while there were no differences between Pro group and control group (P>0.05). But the GPx4mRNA levels were not different between the Se-treatment groups and the control group in the whole experiment period (P>0.05). The results suggest that regulation of GPx1, TR1and GPx4mRNA level by Se are different, Se is more effective in improved GPx1mRNA levels than TR1and GPx4mRNA levels, and the GPx4mRNA levels were not affected by Se status.
Experiment5. Regulation of different mitogens induced T-cell activation by selenium in primary cultured pig splenocytes
In this study, the effects of Se on T-cell proliferation and IL-2production were studied in primary porcine splenocytes. Splenocytes were treated with different mitogens in the presence of0.5-4μmol/L sodium selenite. Se significantly promoted T-cell receptor (TCR) or concanavalin A (ConA)-induced T-cell proliferation and IL-2production but failed to regulate T-cell response to phytohemagglutinin (PHA). In addition, Se significantly increased the levels of cytosolic glutathione peroxidase (GPx1) and thioredoxin reductase1(TR1) mRNA, the activity of GPx1and the concentration of reduced glutathione (GSH) in the unstimulated, or activated splenocytes.These results indicated that Se improved the redox status in all splenocytes, including unstimulated, TCR, ConA and PHA-stimulated, but only TCR and ConA-induced T-cell activation was affected by the redox status. N-acetylcysteine (NAC), a pharmacological antioxidant, increased T-cell proliferation and IL-2production by TCR and ConA stimulated splenocytes but had no effect on the response to PHA in primary porcine splenocytes confirming that PHA-induced T-cell activation is insensitive to the redox status. We conclude that Se promotes GPx1and TR1expression and increases antioxidative capacity in porcine splenocytes, which enhances TCR or ConA-induced T-cell activation but not PHA-induced T-cell activation. The different susceptibilities to Se between the TCR, ConA and PHA-induced T-cell activation may help to explain the controversy in the literature over whether or not Se boosts immune responses.
Experiment6. Effects of different forms and concentrations of selenium on ConA induced T-cell proliferation in primary cultured pig splenocytes
Primary cultured pig splenocytes were incubated with0(control) and vary concentrations of Se as DL-selenomethionine (Se-Met), or sodium selenite (Na2SeO3) for48h in the presence of ConA. Compared to controls, significantly higher T-cell proliferation was observed at0.5-32μmol/L Se-Met, Significant increases of T-cell proliferation were obtained in Na2SeO3treated splenocytes at0.5-4μmol/L, with maximal effects at2μmol/L, and inhibited T-cell proliferation in a dose-dependent manner at8-32μmol/L. Intracellular reduced glutathione (GSH) contents and GPx activity in all Se-treated splenocytes were significantly higher than controls. An increases of GPx1mRNA level were obtained in all Se-treated splenocytes, but GPx4mRNA level was not affected by Se-treatment. And the MS, the inhibitor of the GPx1, significantly inhibited the proliferation improved by Se. We conclude that (i) regulation of ConA induced T-cell proliferation by different Se forms are different in primary cultured pig splenocytes, and GPxl maybe the key enzyme.
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