猪吲哚2，3-二氧化酶介导人血清对猪血管内皮细胞杀伤作用的研究
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摘要
第一部分猪IDO分子的生物信息学预测、克隆及分析
[目的]证明猪IDO基因的存在,分析并克隆猪IDO基因,明确其分子结构特点及表达特性。
[方法]运用生物信息学方法从美国基因数据库(GenBank)获得与人IDO基因同源的猪EST序列,通过RT-PCR技术在猪内皮细胞系SV-40-PED中验证该序列的准确性,对该序列进行生物信息学分析,并研究其组织表达分布特点。利用体细胞杂交板(somatic cell hybrid panel, SCHP)技术对其进行染色体定位。参照人IDO同源分子蛋白的三级结构,利用生物序列分析软件及数据库构建猪IDO蛋白的三维空间结构模型。
[结果]通过克隆测序与同源性分析,发现猪存在IDO分子,将此结果提交至美国基因数据库(GenBank)。DO在猪的胸腺、肺、附睾和眼底中有基础水平的表达,尤其在猪外周血单核/巨噬细胞中表达丰富,IFN-γ刺激后猪血管内皮细胞上可表达IDO。
[结论]生物信息学方法和分子生物学技术的联合使用,有助于猪的新基因的发现与鉴定。本研究证实了猪存在IDO基因的推测,明确了该基因相关的结构信息,为研究猪IDO的免疫学功能奠定了基础。
第二部分猪IDO表达载体的构建、表达
[目的]分别构建高水平表达天然poIDO分子和带标签蛋白的poIDO融合蛋白的重组表达载体。
[方法]利用RT-PCR扩增猪IDO基因片段,连接至T载体,测序无误后,亚克隆至真核表达载体,构建出重组质粒。将重组质粒和空载体分别转染至CHO细胞和PED细胞,用G418进行筛选；通过Western Blot、细胞免疫化学、免疫荧光和流式细胞术等方法检测,鉴定出能稳定表达pcDNA 3.1(-)-poIDO的PED细胞亚群和能稳定表达pCMV-Tag2B-poIDO和pCMV-Tag2B的CHO细胞亚群。
[结果]经过双酶切和测序鉴定,重组质粒pcDNA 3.1(-)-poIDO与pCMV-Tag2B-poIDO构建成功。
[结论]成功构建出能表达天然猪IDO分子的载体质粒pcDNA 3.1(-)-poIDO和能表达出融合蛋白pCMV-Tag2B-poIDO,该蛋白可作为猪IDO介导人血清杀伤猪血管内皮细胞作用研究的重要工具。
第三部分猪IDO介导人血清杀伤猪内皮细胞作用的研究
[目的]研究猪IDO在人血清对猪内皮细胞杀伤效果中的作用,并进一步研究其在这一过程中的作用机制。
[方法]利用流式细胞术检测IDO特异性阻断剂1-MT对人血清对PED杀伤效果的影响,由此初步判断IDO对人血清杀伤猪血管内皮细胞的影响。建立用PI单染法检测人血清对猪血管内皮细胞系(SV-40-PED)细胞毒作用的方法。
[结果]人血清对猪血管内皮细胞的杀伤作用显著；在加入1-MT后,人血清对猪血管内皮细胞的杀伤效果受到抑制。
[结论] IDO促进人血清对猪血管内皮细胞的杀伤作用；PI单染法能够方便客观地检测人血清的杀伤效率。
PartⅠ. Bioinformatics prediction, cloning and characterization of porcine IDO
Objective To confirm the existence of porcine IDO gene, and to clone the novel gene followed by analysis for the molecule structure properties and expression pattern.
Methods The porcine expressed sequence tags(EST) homologous to human IDO were obtained from GenBank database using bioinformatics method. By the way of RT-PCR, the gene was cloned from porcine endothelial cell line(SV-40-PED) and checked for the accuracy of the nucleic acid sequence, then the expression and distribution pattern of the gene was analyzed. Chromosomal localization was performed by means of somatic cell hybrid panel(SCHP). The three-dimension structure model of porcine IDO was built referring to the tertiary structure of human IDO ectodomain using biological sequence analysis softs and database.
Results Porcine IDO was identified by sequencing analysis. The nucleotide sequences were submitted to NCBI database and confirmed as a novel gene. Porcine IDO was expressed in lung、thymus、epididymis and anterior chamber with basic expression level, however in PBMC with high expression level. Chromosomal localization and three-dimension structure model of porcine IDO is yet to be done.
Conclusion Simultaneous utilization of bioinformatics method and molecular biology techniques will conduce the prediction and probation of novel porcine genes, and the presumption about porcine IDO is confirmed by the very way. Identification of the structure information of porcine IDO is essential to further investigate the immunologic function of the gene.
PartⅡ. Construction, expression and purification of porcine pcDNA 3.1(-)-poIDO and pCMV-Tag2B-poIDO fusion protein
Objective To construct the expression vector (pcDNA 3.1(-)-poIDO) and fusion protein of porcine IDO (pCMV-Tag2B-poIDO) which can simulate the natural IDO molecular.
Methods The open reading frame of porcine IDO was amplified from SV-40-PED using RT-PCR and cloned into T vector, then subcloned into eukaryotic expression vector pcDNA 3.1(-) and p CMV-Tag2B after sequencing. The recombinant plasmid pcDNA 3.1(-)-poIDO and the blank vector pcDNA 3.1(-) were transfected into PED cells respectively followed by G418 selection. The recombinant plasmid pCMV-Tag2B-poIDO and the blank vector pCMV-Tag2B were transfected into CHO cells respectively followed by G418 selection. PED cells which can stablely secrete pcDNA 3.1(-)-poIDO protein were identified by the way of Western Blot, immunocytochemistry, immunofluorescence and flow cytometry. And CHO cells which can stablely secrete pCMV-Tag2B-poIDO fusion protein and Tag2B were identified by the way of Western Blot, immunocytochemistry, immunofluorescence and flow cytometry. The fusion protein was purified from the supernatants of the CHO cells culture by protein affinity chromatography.
Results The recombinated plasmid pcDNA 3.1(-)-poIDO、poIDO-pCMV-Tag2B was constructed and verified successfully by double enzyme digestion and sequencing.
Conclusion The vector poIDO-pCMV-Tag2B was obtained successfully and can be used to investigate the interaction between porcine IDO and human serum.
PartⅢ. Study about the effect of poIDO in mediating Xenogeneic cytolytic activity of human serum against porcine endothelial cells
Objective To establish a suitable empirical method to estimate the cytotoxic effect of human serum against porcine endothelial cells objectively.
Methods The effect of 1-MT triggering human serum against porcine endothelial cells was detected by flow cytometry techniques. PI labeling method was established in flow-cytometric human serum cytotoxicity assay.
Results The xenogeneic cytolytic activity of human serum against pocine endothelial cells was inhibited by 1-MT.
Conclusion The xenogeneic cytolytic activity of human serum against pocine endothelial cells was up-regulated by IDO. PI labeling method can test the kill ability of human serum conveniently and objectively.
[目的]证明猪IDO基因的存在,分析并克隆猪IDO基因,明确其分子结构特点及表达特性。
[方法]运用生物信息学方法从美国基因数据库(GenBank)获得与人IDO基因同源的猪EST序列,通过RT-PCR技术在猪内皮细胞系SV-40-PED中验证该序列的准确性,对该序列进行生物信息学分析,并研究其组织表达分布特点。利用体细胞杂交板(somatic cell hybrid panel, SCHP)技术对其进行染色体定位。参照人IDO同源分子蛋白的三级结构,利用生物序列分析软件及数据库构建猪IDO蛋白的三维空间结构模型。
[结果]通过克隆测序与同源性分析,发现猪存在IDO分子,将此结果提交至美国基因数据库(GenBank)。DO在猪的胸腺、肺、附睾和眼底中有基础水平的表达,尤其在猪外周血单核/巨噬细胞中表达丰富,IFN-γ刺激后猪血管内皮细胞上可表达IDO。
[结论]生物信息学方法和分子生物学技术的联合使用,有助于猪的新基因的发现与鉴定。本研究证实了猪存在IDO基因的推测,明确了该基因相关的结构信息,为研究猪IDO的免疫学功能奠定了基础。
第二部分猪IDO表达载体的构建、表达
[目的]分别构建高水平表达天然poIDO分子和带标签蛋白的poIDO融合蛋白的重组表达载体。
[方法]利用RT-PCR扩增猪IDO基因片段,连接至T载体,测序无误后,亚克隆至真核表达载体,构建出重组质粒。将重组质粒和空载体分别转染至CHO细胞和PED细胞,用G418进行筛选；通过Western Blot、细胞免疫化学、免疫荧光和流式细胞术等方法检测,鉴定出能稳定表达pcDNA 3.1(-)-poIDO的PED细胞亚群和能稳定表达pCMV-Tag2B-poIDO和pCMV-Tag2B的CHO细胞亚群。
[结果]经过双酶切和测序鉴定,重组质粒pcDNA 3.1(-)-poIDO与pCMV-Tag2B-poIDO构建成功。
[结论]成功构建出能表达天然猪IDO分子的载体质粒pcDNA 3.1(-)-poIDO和能表达出融合蛋白pCMV-Tag2B-poIDO,该蛋白可作为猪IDO介导人血清杀伤猪血管内皮细胞作用研究的重要工具。
第三部分猪IDO介导人血清杀伤猪内皮细胞作用的研究
[目的]研究猪IDO在人血清对猪内皮细胞杀伤效果中的作用,并进一步研究其在这一过程中的作用机制。
[方法]利用流式细胞术检测IDO特异性阻断剂1-MT对人血清对PED杀伤效果的影响,由此初步判断IDO对人血清杀伤猪血管内皮细胞的影响。建立用PI单染法检测人血清对猪血管内皮细胞系(SV-40-PED)细胞毒作用的方法。
[结果]人血清对猪血管内皮细胞的杀伤作用显著；在加入1-MT后,人血清对猪血管内皮细胞的杀伤效果受到抑制。
[结论] IDO促进人血清对猪血管内皮细胞的杀伤作用；PI单染法能够方便客观地检测人血清的杀伤效率。
PartⅠ. Bioinformatics prediction, cloning and characterization of porcine IDO
Objective To confirm the existence of porcine IDO gene, and to clone the novel gene followed by analysis for the molecule structure properties and expression pattern.
Methods The porcine expressed sequence tags(EST) homologous to human IDO were obtained from GenBank database using bioinformatics method. By the way of RT-PCR, the gene was cloned from porcine endothelial cell line(SV-40-PED) and checked for the accuracy of the nucleic acid sequence, then the expression and distribution pattern of the gene was analyzed. Chromosomal localization was performed by means of somatic cell hybrid panel(SCHP). The three-dimension structure model of porcine IDO was built referring to the tertiary structure of human IDO ectodomain using biological sequence analysis softs and database.
Results Porcine IDO was identified by sequencing analysis. The nucleotide sequences were submitted to NCBI database and confirmed as a novel gene. Porcine IDO was expressed in lung、thymus、epididymis and anterior chamber with basic expression level, however in PBMC with high expression level. Chromosomal localization and three-dimension structure model of porcine IDO is yet to be done.
Conclusion Simultaneous utilization of bioinformatics method and molecular biology techniques will conduce the prediction and probation of novel porcine genes, and the presumption about porcine IDO is confirmed by the very way. Identification of the structure information of porcine IDO is essential to further investigate the immunologic function of the gene.
PartⅡ. Construction, expression and purification of porcine pcDNA 3.1(-)-poIDO and pCMV-Tag2B-poIDO fusion protein
Objective To construct the expression vector (pcDNA 3.1(-)-poIDO) and fusion protein of porcine IDO (pCMV-Tag2B-poIDO) which can simulate the natural IDO molecular.
Methods The open reading frame of porcine IDO was amplified from SV-40-PED using RT-PCR and cloned into T vector, then subcloned into eukaryotic expression vector pcDNA 3.1(-) and p CMV-Tag2B after sequencing. The recombinant plasmid pcDNA 3.1(-)-poIDO and the blank vector pcDNA 3.1(-) were transfected into PED cells respectively followed by G418 selection. The recombinant plasmid pCMV-Tag2B-poIDO and the blank vector pCMV-Tag2B were transfected into CHO cells respectively followed by G418 selection. PED cells which can stablely secrete pcDNA 3.1(-)-poIDO protein were identified by the way of Western Blot, immunocytochemistry, immunofluorescence and flow cytometry. And CHO cells which can stablely secrete pCMV-Tag2B-poIDO fusion protein and Tag2B were identified by the way of Western Blot, immunocytochemistry, immunofluorescence and flow cytometry. The fusion protein was purified from the supernatants of the CHO cells culture by protein affinity chromatography.
Results The recombinated plasmid pcDNA 3.1(-)-poIDO、poIDO-pCMV-Tag2B was constructed and verified successfully by double enzyme digestion and sequencing.
Conclusion The vector poIDO-pCMV-Tag2B was obtained successfully and can be used to investigate the interaction between porcine IDO and human serum.
PartⅢ. Study about the effect of poIDO in mediating Xenogeneic cytolytic activity of human serum against porcine endothelial cells
Objective To establish a suitable empirical method to estimate the cytotoxic effect of human serum against porcine endothelial cells objectively.
Methods The effect of 1-MT triggering human serum against porcine endothelial cells was detected by flow cytometry techniques. PI labeling method was established in flow-cytometric human serum cytotoxicity assay.
Results The xenogeneic cytolytic activity of human serum against pocine endothelial cells was inhibited by 1-MT.
Conclusion The xenogeneic cytolytic activity of human serum against pocine endothelial cells was up-regulated by IDO. PI labeling method can test the kill ability of human serum conveniently and objectively.
引文
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