IL-18和IL-18BP融合蛋白在不同载体中的表达和纯化
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摘要
白细胞介素18是白细胞介素1家庭的一位独特的家族成员。它与白细胞介素1在结构上很相似,都是需要caspase-1才能使之前体变成有活性的因子。IL-18作为一种细胞因子可以诱生IFN-γ、增强NK细胞细胞毒性作用、增强NK细胞活性、增强Th1型免疫反应、抗肿瘤作用等多种生物功能。白介素18结合蛋白(IL-18BP)是新近发现的一种糖蛋白,属免疫球蛋白超家族成员,目前已发现有6种IL-8BP的同工蛋白。IL-18BP可以在体内外有效抑制IL-18的作用,因而被认为是IL-18的天然拮抗剂。
以往对IL-18和IL-18BP的研究分析只限于某个载体,没有专门针对原核系统、没有专门为了获取融合性蛋白而进行的。也没有在诱导表达和纯化的过程中,对IL-18和IL-18BP这两个天然拮抗剂进行专门的统一的分析,没有把他们的缓冲环境、融合蛋白诱导条件和洗杂、洗脱环境总结为共同的一个模式。IL-18和IL-18BP都存在于动物体内,因此对同一环境下的研究就显得十分有意义。本次实验对原核系统进行了表达和纯化,并以获得融合蛋白为目的,不断的探讨能够表达出融合蛋白的方法,同时对IL-18和IL-18BP表达、纯化条件进行比较,是一个纵向从PCR到纯化,横向从IL-18到IL-18BP的新的研究方法。它们在结构上虽然有一定程度的相似。但是还是相差很远,对它们表达和纯化的共同模式的摸索可能对它们作用机理、在动物体内的相互作用制衡的研究提供帮助。IL-18BP是IL-18的天然拮抗剂,由于他们都具有免疫的双向调节作用,所以在疾病的过程中通过两者的平衡,到达治疗和预防疾病的作用,那么本次实验的研究可能会对二者在共同的环境-动物体内平衡的研究具有一定程度上的意义。同时也将为基础兽医学和兽医免疫学提供新的科学研究依据,产生重要的影响。
实验研究采用PCR扩增出人白细胞介素18和人白细胞介素18结合蛋白的DNA,克隆到原核表达载体PET28a和Pgex-6p-1中,转化大肠杆菌BL21。在原核系统(BL21)中表达并纯化人白细胞介素18和白细胞介素18结合蛋白。探讨了PCR、酶切、连接、转化、诱导表达和纯化方面的实验过程和注意事项,从而展示了原核表达系统从PCR到纯化更加清晰的思路,同时也对蛋白序列进行了一定的分析,通过分析得出消光系数等数据,再同层析系统所提供的数据结合,计算出了蛋白的浓度,最后将蛋白进行浓缩,保存在-80℃。也从菌中提取了重组质粒,保存起来,以便日后方便使用。
实验运用gene runner软件设计好了引物,根据基因的特点和性质,选择了BamHⅠ和EcoRⅠ两个酶切位点,因为它们有共同的缓冲环境,进而确定了PET28a和Pgex-6p-1作为载体。根据菌体的性质,优化了质粒提取的效率。实验为了提高连接的效率,采用过夜连接,确保连接的成功。转化过程避开了震动,热击时间过长等一系列的干扰因素,使得实验能够顺利进行。诱导表达时严格控制时间,菌液的0D值等,避免了表达过程可能丢失重组质粒、噬菌体干扰,其他菌类的滋长等情况的发生。对于最佳的诱导浓度的摸索,采用了纵横交叉的梯度摸索,尽可能的找到诱导出融合蛋白的条件。为了避免在上层析系统时RNA对吸收峰的影响和蛋白的降解,事先在缓冲液中加入了PNA酶和还原剂。根据层析系统所得到的信息,进一步提纯蛋白。
白细胞介素18(IL-18)和白介素18结合蛋白(IL-18BP)的研究对肿瘤疾病、自身免疫性疾病感染性疾病、移植物抗宿主病、代谢综合征、过敏性疾病的治疗和它们的发病机理都有很大的帮助。纯化出来的蛋白无论去做免疫活性的测定、单克隆抗体的制备,上细胞实验、上动物实验,还是用于疾病的治疗以及疾病研究都具有很广阔的意义。为疾病治疗尤其是肿瘤治疗提供了新的途径。为基础兽医学和兽医免疫学提供新的科学研究依据,产生重要的影响。
IL-18 is a special member of the IL-1 family,which closely related to IL-1 in structure and require easpase-1 as an activing agent.Interleukin(IL)-18 was identified as an cell factor that induces the produce of interferon-gamma,enhances NK cell cytotoxicity,mprove the activity of natural killer cells as well as Thl immunoreation type and and fulls of antieancer effects and so on.Interleukin-18 binding protein(IL-18BP)is a novel glycoprotein and belongs to the immunoglobulin superfamily.So far,six IL-18BP isoforms have been found in various eDNA libraries.IL-18BP is regarded as a natural antagonist for IL-18 which efficiently inhibits the biological functions of IL—18 in vitro an d in vivo.
Formerly,the research and analysis of IL-18 and the IL-18BP were only restricted in some vector,has not carry specially on almming at the nucleus system,and at gainning the fusion protein,also has not carry specially on unified analysis to these two natural antagonist compounds-IL-18 and IL-18BP in the induction expresses and purification,has not summarize mixed theirs cushion environment,inducting condition of the fusion protein,washes,the elution environment for a common pattern.IL-18 and IL-18BP exist in animal's vivo,therefore it appears very meaningful to research under the identical environment.The experiment uses analysis vertically and horizontally,longitudinal is form PCR to the purification,crosswise is form IL-18 to IL-18BP,although they has the certain similitude in structure,but their difference is very far,the scrabble between them that can use the common pattern is possibly to provide the help for their action mechanism,the research which keeps in balance in the animal in vivo's interaction. IL-18BP is the natural antagonist compound of IL-18,because they have the immune bidirectional adjust action,therefore in disease's process through beth's balanced,achieve the treatment and prevent disease's function,then this experiment's research is possibly to have the certain extent significance in the common environment - balance of animal in vivo.Simultaneously,it also will provide the new scientific research basis for the foundation veterinary science and the veterinarian immunology,will have the important influence.
The experimental study used PCR to amplify the eDNA of human interleukin 18 and Interleukin-18 binding protein and then that were cloned into the expression vector PET28a and Pgex-6p-1,transformed into the E.coli BL21.expressed and purified the reeomabinant human interleukin 18 and Intefleukin-18 binding protein in prokaryofic system(BL21).This article discuss experimental technique and matters needing attention in experiment process about PCR,the enzyme outed,Connection,transformation,inducted expression and purification.Thus,it demonstrates clearer mentality form PCR to purification about prokaryofic system, Simultaneously it has also carried on certain analysis to the protein sequence,Obtains data and so on extinction coefficient through the analysis,Again data union which provides with the chromatographic analysis system,calculated the protein density,finally carried on the protein the concentration,Preservated in - 80℃.It has also withdrawn the Clone from the fungus, preserves,with the aim of facilitating in the future uses.
The experiment has designed the primers through the software-gene gunner,According to the gene characteristic and the nature,chose two enzymes to cut the position spot -BamH I and EeoRI.Because they have the common cushion environment,then we had determined that PET28a and Pgex-6p-1 are the vectors.According to mycelium's nature,we optimized the Clone's extraction efficiency.The experiment to enhance the connection's efficiency,uses the over night connection,guarantees the connection's succession.The transforming process avoided the vibration,the over time heat's strucking and so on a series of disturbance factor,enabled the experiment to be able to carry on smoothly.When inducting expression,we controlled the time strictly,the vaccine OD value and so on,avoided some tings in the expression process that it is losing the clone,the bacteriophage disturbance,other fungus categories developed and so on situation occurrences.Regarding the best induction density's fumble,we used vertically and horizontally the overlapping gradient to try to find out as far as possible the condition.that induces the fusion protein.In order to avoid the influence of the absorbing peak to RNA and the protein's degeneration when we used the chromatographically analyzes system,we had joined the RNA enzyme and the reducing agent beforehand in the buffer solution,according to information which obtains form the chromatographic analysis system,we can deputes the protein further.
The research of interleukin-18 and Interleukin-18 binding protein has very big help in the treatment of tumor disease,own immunity vigorous sickness,infectious disease,transplant anti-host sickness,metabolism syndrome,allergic disease and their pathogenesis,the purified protein regardless of makeing the immunity active determination,specific monoclonal antibodies preparation,useing in the cell experiment,using in the animal experimentation,as well as,useing in the illness treatment and the illness research that gets sick has the very broad significance. Treating disease Specially the tumor treatment,it provide the new way.
以往对IL-18和IL-18BP的研究分析只限于某个载体,没有专门针对原核系统、没有专门为了获取融合性蛋白而进行的。也没有在诱导表达和纯化的过程中,对IL-18和IL-18BP这两个天然拮抗剂进行专门的统一的分析,没有把他们的缓冲环境、融合蛋白诱导条件和洗杂、洗脱环境总结为共同的一个模式。IL-18和IL-18BP都存在于动物体内,因此对同一环境下的研究就显得十分有意义。本次实验对原核系统进行了表达和纯化,并以获得融合蛋白为目的,不断的探讨能够表达出融合蛋白的方法,同时对IL-18和IL-18BP表达、纯化条件进行比较,是一个纵向从PCR到纯化,横向从IL-18到IL-18BP的新的研究方法。它们在结构上虽然有一定程度的相似。但是还是相差很远,对它们表达和纯化的共同模式的摸索可能对它们作用机理、在动物体内的相互作用制衡的研究提供帮助。IL-18BP是IL-18的天然拮抗剂,由于他们都具有免疫的双向调节作用,所以在疾病的过程中通过两者的平衡,到达治疗和预防疾病的作用,那么本次实验的研究可能会对二者在共同的环境-动物体内平衡的研究具有一定程度上的意义。同时也将为基础兽医学和兽医免疫学提供新的科学研究依据,产生重要的影响。
实验研究采用PCR扩增出人白细胞介素18和人白细胞介素18结合蛋白的DNA,克隆到原核表达载体PET28a和Pgex-6p-1中,转化大肠杆菌BL21。在原核系统(BL21)中表达并纯化人白细胞介素18和白细胞介素18结合蛋白。探讨了PCR、酶切、连接、转化、诱导表达和纯化方面的实验过程和注意事项,从而展示了原核表达系统从PCR到纯化更加清晰的思路,同时也对蛋白序列进行了一定的分析,通过分析得出消光系数等数据,再同层析系统所提供的数据结合,计算出了蛋白的浓度,最后将蛋白进行浓缩,保存在-80℃。也从菌中提取了重组质粒,保存起来,以便日后方便使用。
实验运用gene runner软件设计好了引物,根据基因的特点和性质,选择了BamHⅠ和EcoRⅠ两个酶切位点,因为它们有共同的缓冲环境,进而确定了PET28a和Pgex-6p-1作为载体。根据菌体的性质,优化了质粒提取的效率。实验为了提高连接的效率,采用过夜连接,确保连接的成功。转化过程避开了震动,热击时间过长等一系列的干扰因素,使得实验能够顺利进行。诱导表达时严格控制时间,菌液的0D值等,避免了表达过程可能丢失重组质粒、噬菌体干扰,其他菌类的滋长等情况的发生。对于最佳的诱导浓度的摸索,采用了纵横交叉的梯度摸索,尽可能的找到诱导出融合蛋白的条件。为了避免在上层析系统时RNA对吸收峰的影响和蛋白的降解,事先在缓冲液中加入了PNA酶和还原剂。根据层析系统所得到的信息,进一步提纯蛋白。
白细胞介素18(IL-18)和白介素18结合蛋白(IL-18BP)的研究对肿瘤疾病、自身免疫性疾病感染性疾病、移植物抗宿主病、代谢综合征、过敏性疾病的治疗和它们的发病机理都有很大的帮助。纯化出来的蛋白无论去做免疫活性的测定、单克隆抗体的制备,上细胞实验、上动物实验,还是用于疾病的治疗以及疾病研究都具有很广阔的意义。为疾病治疗尤其是肿瘤治疗提供了新的途径。为基础兽医学和兽医免疫学提供新的科学研究依据,产生重要的影响。
IL-18 is a special member of the IL-1 family,which closely related to IL-1 in structure and require easpase-1 as an activing agent.Interleukin(IL)-18 was identified as an cell factor that induces the produce of interferon-gamma,enhances NK cell cytotoxicity,mprove the activity of natural killer cells as well as Thl immunoreation type and and fulls of antieancer effects and so on.Interleukin-18 binding protein(IL-18BP)is a novel glycoprotein and belongs to the immunoglobulin superfamily.So far,six IL-18BP isoforms have been found in various eDNA libraries.IL-18BP is regarded as a natural antagonist for IL-18 which efficiently inhibits the biological functions of IL—18 in vitro an d in vivo.
Formerly,the research and analysis of IL-18 and the IL-18BP were only restricted in some vector,has not carry specially on almming at the nucleus system,and at gainning the fusion protein,also has not carry specially on unified analysis to these two natural antagonist compounds-IL-18 and IL-18BP in the induction expresses and purification,has not summarize mixed theirs cushion environment,inducting condition of the fusion protein,washes,the elution environment for a common pattern.IL-18 and IL-18BP exist in animal's vivo,therefore it appears very meaningful to research under the identical environment.The experiment uses analysis vertically and horizontally,longitudinal is form PCR to the purification,crosswise is form IL-18 to IL-18BP,although they has the certain similitude in structure,but their difference is very far,the scrabble between them that can use the common pattern is possibly to provide the help for their action mechanism,the research which keeps in balance in the animal in vivo's interaction. IL-18BP is the natural antagonist compound of IL-18,because they have the immune bidirectional adjust action,therefore in disease's process through beth's balanced,achieve the treatment and prevent disease's function,then this experiment's research is possibly to have the certain extent significance in the common environment - balance of animal in vivo.Simultaneously,it also will provide the new scientific research basis for the foundation veterinary science and the veterinarian immunology,will have the important influence.
The experimental study used PCR to amplify the eDNA of human interleukin 18 and Interleukin-18 binding protein and then that were cloned into the expression vector PET28a and Pgex-6p-1,transformed into the E.coli BL21.expressed and purified the reeomabinant human interleukin 18 and Intefleukin-18 binding protein in prokaryofic system(BL21).This article discuss experimental technique and matters needing attention in experiment process about PCR,the enzyme outed,Connection,transformation,inducted expression and purification.Thus,it demonstrates clearer mentality form PCR to purification about prokaryofic system, Simultaneously it has also carried on certain analysis to the protein sequence,Obtains data and so on extinction coefficient through the analysis,Again data union which provides with the chromatographic analysis system,calculated the protein density,finally carried on the protein the concentration,Preservated in - 80℃.It has also withdrawn the Clone from the fungus, preserves,with the aim of facilitating in the future uses.
The experiment has designed the primers through the software-gene gunner,According to the gene characteristic and the nature,chose two enzymes to cut the position spot -BamH I and EeoRI.Because they have the common cushion environment,then we had determined that PET28a and Pgex-6p-1 are the vectors.According to mycelium's nature,we optimized the Clone's extraction efficiency.The experiment to enhance the connection's efficiency,uses the over night connection,guarantees the connection's succession.The transforming process avoided the vibration,the over time heat's strucking and so on a series of disturbance factor,enabled the experiment to be able to carry on smoothly.When inducting expression,we controlled the time strictly,the vaccine OD value and so on,avoided some tings in the expression process that it is losing the clone,the bacteriophage disturbance,other fungus categories developed and so on situation occurrences.Regarding the best induction density's fumble,we used vertically and horizontally the overlapping gradient to try to find out as far as possible the condition.that induces the fusion protein.In order to avoid the influence of the absorbing peak to RNA and the protein's degeneration when we used the chromatographically analyzes system,we had joined the RNA enzyme and the reducing agent beforehand in the buffer solution,according to information which obtains form the chromatographic analysis system,we can deputes the protein further.
The research of interleukin-18 and Interleukin-18 binding protein has very big help in the treatment of tumor disease,own immunity vigorous sickness,infectious disease,transplant anti-host sickness,metabolism syndrome,allergic disease and their pathogenesis,the purified protein regardless of makeing the immunity active determination,specific monoclonal antibodies preparation,useing in the cell experiment,using in the animal experimentation,as well as,useing in the illness treatment and the illness research that gets sick has the very broad significance. Treating disease Specially the tumor treatment,it provide the new way.
引文
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