小鼠甘露糖受体CR、CTLD_(4-7)结构域表达条件的优化和功能的初步研究
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摘要
甘露糖受体(Mannose receptor, MR)是甘露糖受体家族成员之一,属于C型凝集素超家族,是甘露糖受体家族最早被发现的成员,分子量为175kDa。已经发现,甘露糖受体表达于巨噬细胞、肝内皮细胞、淋巴内皮细胞和肾小球系膜细胞上。甘露糖受体是典型的Ⅰ型跨膜蛋白,由胞外区、跨膜区和胞内区组成。其胞外区含有三个结构域,由N端起依次为富含半胱氨酸结构域(Cystein rich, CR)、Ⅱ型纤连蛋白结构域FN和8个连续的C-型凝集素结构域(C-type lectin domain,CTLD )。CR能结合SO4-3-Gal、SO4-3/4-GalNAc为末端的糖配体;FN参与胶原蛋白的结合,特别是胶原蛋白Ⅰ、Ⅱ、Ⅲ、Ⅳ;CRD能结合甘露糖、岩藻糖和N-乙酰葡糖胺为末端的糖配体。甘露糖受体胞内区介导受体的内吞和质膜循环。甘露糖受体能介导内源分子的清除,在病原体的识别、抗原提呈和淋巴细胞的黏附中起重要作用。MR还表达在输入和输出淋巴管上,参与某些淋巴细胞和肿瘤细胞对淋巴组织的黏附过程。
L-选择蛋白作为细胞粘附分子,存在于大多数白细胞表面,参与白细胞在淋巴内皮上的滚动、黏附和迁移。体外实验表明L-选择蛋白能与输出淋巴管上的甘露糖受体结合,表达L-选择蛋白的淋巴细胞能通过这种方式输出淋巴组织。某些表达L-选择蛋白的肿瘤细胞可能通过L-选择蛋白与淋巴管内皮上的甘露糖受体相互作用参与肿瘤的淋巴道转移。然而,甘露糖受体与L-选择蛋白相互作用的部位尚未阐明,甘露糖受体与L-选择蛋白的相互作用与肿瘤经淋巴道转移的关系,还有待进一步研究。
本实验室的前期工作构建了小鼠甘露糖受体CR结构域或CTLD4-7结构域与人IgG Fc段融合蛋白真核细胞表达载体,转染其至293T细胞中表达,并从培养上清中,纯化得到了重组小鼠甘露糖受体CR结构域与人IgG Fc段嵌合蛋白。
目的:
本研究将优化小鼠甘露糖受体CR结构域与人IgG Fc段嵌合蛋白在真核细胞的表达条件;从转染的细胞培养基中纯化两种蛋白。利用体外黏附实验和流式细胞仪检测,在蛋白质和细胞水平上研究甘露糖受体与L-选择蛋白之间的相互识别。
方法:
将构建好的pCDNA3.1/sig-CR-Fc、pCDNA3.1/sig-CTLD4-7-Fc真核表达载体用Lipofectamine 2000转染至真核细胞中(293T或COS-7),通过ELISA和免疫细胞化学的方法鉴定融合蛋白的表达量,并优化表达条件。收集大量转染后的培养基,用Protein A亲和层析纯化融合蛋白,SDS-PAGE和Western Blot鉴定。
将纯化后的CR-Fc融合蛋白与稳定表达L-选择蛋白的小鼠肝癌Hepa1-6细胞进行体外黏附实验,Hepa1-6细胞作对照。同时还与小鼠淋巴瘤P388D1细胞、稳定表达L-选择蛋白的Hepa1-6细胞共孵育,流式细胞仪检测CR-Fc融合蛋白与细胞表面的识别。
结果:
1.优化了CR-Fc融合蛋白在293T细胞中的表达条件,获得了更高效的表达,并且在整个转染过程中未使用血清,SDS-PAGE电泳后,考马斯亮蓝染色后呈单一条带,分子量在50 kDa。
2.体外黏附实验证明CR-Fc融合蛋白能促进稳定表达L-选择蛋白的Hepa1-6细胞的黏附。
3.流式细胞仪检测表明细胞表面表达的L-选择蛋白能与CR-Fc融合蛋白相互识别。
4.免疫细胞化学和Western Blot鉴定,CTLD4-7-Fc融合蛋白成功的在COS-7细胞中表达,为进一步纯化奠定了基础。
结论:
甘露糖受体CR结构域能与L-选择蛋白相互识别,并能促进表面表达L-选择蛋白的细胞黏附。
The mannose receptor(MR, CD206) is a member of the MR family which is a subgroup of the C-type lectin superfamily. MR was the first MR family member to be discovered as a 175kDa endocytic receptor. MR expression is not MΦ-restricted; it is also expressed by hepatic and lymphatic endothelia and kidney mesangial cells. MR is a type-Ⅰmembrane protein with a single transmembrane domain and a cytoplasmic domain that mediates receptor internalisation and recycling. It contains three types of domains at its extracellular region, an N-terminal cysteine-rich(CR) domain capable of binding to sulphated sugar terminated in SO4-3-Gal or SO4-3/4-GalNAc, a fibronectin typeⅡ(FNⅡ) domain involved in collagen binding especially collagen typeⅠ,Ⅱ,Ⅲ,andⅣ, and eight CTLD responsible for binding to sugars terminated in mannose, fucose or N-acetyl glucosamine. MR mediates efficient clearance of endogenous molecules and could play a role in microbial recognization and antigen presentation and lymphocyte adhesion. In vitro studies have suggested that MR is abundantly present on both afferent and efferent lymphatic. Furthermore, both lymphocytes and some tumor cells bind to lymphatic tissues in an MR-dependent fashion. MR may serve as an adhesion molecule during cell migration to lymph nodes.
L-selectin is a cell adhesion molecule expressed on the surface of most leukocytes and involved their rolling on inflamed vascular endothelium to promote to firm adhesion and transmigration. The study also showed that L-selectin can bind to MR expressed on efferent lymphatic sinuses, which mediates lymphocytes leaving the peripheral tissues via afferent lymphatic. It was suggested that the L-selectin positive tumor cells can interact with MR on the surface of lymphatic endothelial and contribute to tumor lymphatic metastasis.
Previously studies in our lab showed that silencing the expression of L-selectin on P388D1 cells attenuated the P388D1 cell metastasis via lymphatic vessels. To understand the role of mannose receptor and L-selectin in lymphatic metastasis, the Plasmids encoding the Fc chimeric proteins containing CR or CTLD4-7 were constructed. Our preliminary data showed the CR-Fc and CTLD4-7-Fc could be expressed in COS-7 cells.
Objective:
This study is to optimize the condition for expression of the chimeric proteins containing CR or CTLD4-7 fused to the Fc region of human IgG (CR-Fc/CTLD4-7-Fc), to purify them from supernatants of transfected cells, to identify their interaction and to explore the role of mannose receptor and L-selectin in tumor lymphatic metastasis.
Methods:
Plasmids encoding the Fc chimeric proteins containing CR or CTLD4-7 were introduced into the 293T or COS-7 cell line by transient transfection with Lipofectamine 2000 following manufacturer's instruction. Immuno- cytochemical analysis and ELISA were used to detect the expression of the chimeric proteins and optimize the expression conditions. The recombinant CR-Fc chimeric protein was purified by Protein A chromatography from abundant culture supernatants and identified with SDS-PAGE and Western Blot analysis.
The interaction between CR-Fc chimeric protein and L-selectin on P388D1 cells and Hepa1-6/L-selectin cells were analyzed by cell adhesion assays and flow cytometry analysis. IgG protein and Hepa1-6 cells were used as control.
Results:
1. The condition for more efficient expression of CR-Fc and CTLD4-7-Fc chimeric protein was optimized. CR-Fc chimeric protein was purified and exhibited as a single band with a molecular mass of 50 kDa on reducing SDS-PAGE.
2. Cell adhesion assay in vitro proved that Hepa1-6/L-selectin cells specifically attached CR-Fc chimeric protein coated at the bottom of 96 well plate, compared with Hepa1-6 cells (p<0.05).
3. Flow cytometry analysis indicated that CR-Fc chimeric protein specifily recognized L-selectin on the surface of P388D1cells, compared with IgG protein (p<0.05).
4. Immunofluorescence assay and Western blot analysis demonstrated that CTLD4-7-Fc chimeric protein was expressed abundantly in COS-7 cells, which provided a foundation for the future purification.
Conclusions:
The CR domain of mannose receptor could recognize and attach L-selectin on the cell surface, which may partly elucidate that the interaction between Mannose receptor and L-selectin is involved in the lymphatic metastasis.
L-选择蛋白作为细胞粘附分子,存在于大多数白细胞表面,参与白细胞在淋巴内皮上的滚动、黏附和迁移。体外实验表明L-选择蛋白能与输出淋巴管上的甘露糖受体结合,表达L-选择蛋白的淋巴细胞能通过这种方式输出淋巴组织。某些表达L-选择蛋白的肿瘤细胞可能通过L-选择蛋白与淋巴管内皮上的甘露糖受体相互作用参与肿瘤的淋巴道转移。然而,甘露糖受体与L-选择蛋白相互作用的部位尚未阐明,甘露糖受体与L-选择蛋白的相互作用与肿瘤经淋巴道转移的关系,还有待进一步研究。
本实验室的前期工作构建了小鼠甘露糖受体CR结构域或CTLD4-7结构域与人IgG Fc段融合蛋白真核细胞表达载体,转染其至293T细胞中表达,并从培养上清中,纯化得到了重组小鼠甘露糖受体CR结构域与人IgG Fc段嵌合蛋白。
目的:
本研究将优化小鼠甘露糖受体CR结构域与人IgG Fc段嵌合蛋白在真核细胞的表达条件;从转染的细胞培养基中纯化两种蛋白。利用体外黏附实验和流式细胞仪检测,在蛋白质和细胞水平上研究甘露糖受体与L-选择蛋白之间的相互识别。
方法:
将构建好的pCDNA3.1/sig-CR-Fc、pCDNA3.1/sig-CTLD4-7-Fc真核表达载体用Lipofectamine 2000转染至真核细胞中(293T或COS-7),通过ELISA和免疫细胞化学的方法鉴定融合蛋白的表达量,并优化表达条件。收集大量转染后的培养基,用Protein A亲和层析纯化融合蛋白,SDS-PAGE和Western Blot鉴定。
将纯化后的CR-Fc融合蛋白与稳定表达L-选择蛋白的小鼠肝癌Hepa1-6细胞进行体外黏附实验,Hepa1-6细胞作对照。同时还与小鼠淋巴瘤P388D1细胞、稳定表达L-选择蛋白的Hepa1-6细胞共孵育,流式细胞仪检测CR-Fc融合蛋白与细胞表面的识别。
结果:
1.优化了CR-Fc融合蛋白在293T细胞中的表达条件,获得了更高效的表达,并且在整个转染过程中未使用血清,SDS-PAGE电泳后,考马斯亮蓝染色后呈单一条带,分子量在50 kDa。
2.体外黏附实验证明CR-Fc融合蛋白能促进稳定表达L-选择蛋白的Hepa1-6细胞的黏附。
3.流式细胞仪检测表明细胞表面表达的L-选择蛋白能与CR-Fc融合蛋白相互识别。
4.免疫细胞化学和Western Blot鉴定,CTLD4-7-Fc融合蛋白成功的在COS-7细胞中表达,为进一步纯化奠定了基础。
结论:
甘露糖受体CR结构域能与L-选择蛋白相互识别,并能促进表面表达L-选择蛋白的细胞黏附。
The mannose receptor(MR, CD206) is a member of the MR family which is a subgroup of the C-type lectin superfamily. MR was the first MR family member to be discovered as a 175kDa endocytic receptor. MR expression is not MΦ-restricted; it is also expressed by hepatic and lymphatic endothelia and kidney mesangial cells. MR is a type-Ⅰmembrane protein with a single transmembrane domain and a cytoplasmic domain that mediates receptor internalisation and recycling. It contains three types of domains at its extracellular region, an N-terminal cysteine-rich(CR) domain capable of binding to sulphated sugar terminated in SO4-3-Gal or SO4-3/4-GalNAc, a fibronectin typeⅡ(FNⅡ) domain involved in collagen binding especially collagen typeⅠ,Ⅱ,Ⅲ,andⅣ, and eight CTLD responsible for binding to sugars terminated in mannose, fucose or N-acetyl glucosamine. MR mediates efficient clearance of endogenous molecules and could play a role in microbial recognization and antigen presentation and lymphocyte adhesion. In vitro studies have suggested that MR is abundantly present on both afferent and efferent lymphatic. Furthermore, both lymphocytes and some tumor cells bind to lymphatic tissues in an MR-dependent fashion. MR may serve as an adhesion molecule during cell migration to lymph nodes.
L-selectin is a cell adhesion molecule expressed on the surface of most leukocytes and involved their rolling on inflamed vascular endothelium to promote to firm adhesion and transmigration. The study also showed that L-selectin can bind to MR expressed on efferent lymphatic sinuses, which mediates lymphocytes leaving the peripheral tissues via afferent lymphatic. It was suggested that the L-selectin positive tumor cells can interact with MR on the surface of lymphatic endothelial and contribute to tumor lymphatic metastasis.
Previously studies in our lab showed that silencing the expression of L-selectin on P388D1 cells attenuated the P388D1 cell metastasis via lymphatic vessels. To understand the role of mannose receptor and L-selectin in lymphatic metastasis, the Plasmids encoding the Fc chimeric proteins containing CR or CTLD4-7 were constructed. Our preliminary data showed the CR-Fc and CTLD4-7-Fc could be expressed in COS-7 cells.
Objective:
This study is to optimize the condition for expression of the chimeric proteins containing CR or CTLD4-7 fused to the Fc region of human IgG (CR-Fc/CTLD4-7-Fc), to purify them from supernatants of transfected cells, to identify their interaction and to explore the role of mannose receptor and L-selectin in tumor lymphatic metastasis.
Methods:
Plasmids encoding the Fc chimeric proteins containing CR or CTLD4-7 were introduced into the 293T or COS-7 cell line by transient transfection with Lipofectamine 2000 following manufacturer's instruction. Immuno- cytochemical analysis and ELISA were used to detect the expression of the chimeric proteins and optimize the expression conditions. The recombinant CR-Fc chimeric protein was purified by Protein A chromatography from abundant culture supernatants and identified with SDS-PAGE and Western Blot analysis.
The interaction between CR-Fc chimeric protein and L-selectin on P388D1 cells and Hepa1-6/L-selectin cells were analyzed by cell adhesion assays and flow cytometry analysis. IgG protein and Hepa1-6 cells were used as control.
Results:
1. The condition for more efficient expression of CR-Fc and CTLD4-7-Fc chimeric protein was optimized. CR-Fc chimeric protein was purified and exhibited as a single band with a molecular mass of 50 kDa on reducing SDS-PAGE.
2. Cell adhesion assay in vitro proved that Hepa1-6/L-selectin cells specifically attached CR-Fc chimeric protein coated at the bottom of 96 well plate, compared with Hepa1-6 cells (p<0.05).
3. Flow cytometry analysis indicated that CR-Fc chimeric protein specifily recognized L-selectin on the surface of P388D1cells, compared with IgG protein (p<0.05).
4. Immunofluorescence assay and Western blot analysis demonstrated that CTLD4-7-Fc chimeric protein was expressed abundantly in COS-7 cells, which provided a foundation for the future purification.
Conclusions:
The CR domain of mannose receptor could recognize and attach L-selectin on the cell surface, which may partly elucidate that the interaction between Mannose receptor and L-selectin is involved in the lymphatic metastasis.
引文
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1 . Katie M. Jansen, Grace K. Pavlath. et al. Mannose receptor regulates myoblast motility and muscle growth. JCB.2006,174 (3):403-413
2 . Irjala H, Johansson, et al. Mannose receptor is a novel ligand for L-selectin and mediates lymphocyte binding to lymphatic endothelium. J Exp Med.2001, 194, 1033–1042.
3 . Heikki Irjala, Kalle Alanen, et al. Mannose Receptor (MR) and Common Lymphatic Endothelial and Vascular Endothelial Receptor (CLEVER)-1 Direct the Binding of Cancer Cells to the Lymph Vessel Endothelium.Cancer Research. 2003, 63, 4671-4676
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5 . Fumiko MI, Raisa T,et al. Macrophage mannose receptor on lymphatics controls cell trafficking. Blood. 2008,112(1):64-72
6 .左云飞. L-选择蛋白与P388D1淋巴瘤细胞淋巴道转移潜能的相关性[D].大连医科大学.2006
7 .刘敏,王莉芬,朱杰等.L-选择蛋白可能介导小鼠肝癌细胞经淋巴道转移的研究.解剖学报.35(5):502-506. 2004
8 .刘敏,朱杰,杨佩满等.L-选择蛋白在小鼠肝癌细胞Hca-F和Hca-P的表达及与肿瘤转移潜能的相关性.解剖科学进展.9(2):100-104. 2003
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1 0 . Luisa MP, Paul R Crocker, Rosangela DS, Nick H, Cristina C, Pauline R, Raymond D, Siamon G. Cell-specific Glycoforms of Sialoadhesin and CD45 Are Counterreceptors for the Cysteine-rich Domain of the Mannose Receptor. The journal of biological chemistry. 1999;274(49):35211–218
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1 3 .刘芯宇.L-选择蛋白与小鼠肝癌细胞Hepa1-6淋巴道转移潜能的相关性.大连医科大学硕士论文
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45.刘敏,王莉芬,朱杰等.L-选择蛋白可能介导小鼠肝癌细胞经淋巴道转移的研究.解剖学报.2004, 35(5), 502-506
46.刘敏,朱杰,杨佩满等.L-选择蛋白在小鼠肝癌细胞Hca-F和Hca-P的表达及与肿瘤转移潜能的相关性.解剖科学进展.2003, 9(2), 100-104
1 . Katie M. Jansen, Grace K. Pavlath. et al. Mannose receptor regulates myoblast motility and muscle growth. JCB.2006,174 (3):403-413
2 . Irjala H, Johansson, et al. Mannose receptor is a novel ligand for L-selectin and mediates lymphocyte binding to lymphatic endothelium. J Exp Med.2001, 194, 1033–1042.
3 . Heikki Irjala, Kalle Alanen, et al. Mannose Receptor (MR) and Common Lymphatic Endothelial and Vascular Endothelial Receptor (CLEVER)-1 Direct the Binding of Cancer Cells to the Lymph Vessel Endothelium.Cancer Research. 2003, 63, 4671-4676
4 . Martens JH, Kzhyshkowska J, Falkowski Hansen M, et al. Differential expression of a gene signature for scavenger/lectin receptors by endothelial cells and macrophages in human lymph node sinuses, the primary sites of regional metastasis.2006,208(4),574-589
5 . Fumiko MI, Raisa T,et al. Macrophage mannose receptor on lymphatics controls cell trafficking. Blood. 2008,112(1):64-72
6 .左云飞. L-选择蛋白与P388D1淋巴瘤细胞淋巴道转移潜能的相关性[D].大连医科大学.2006
7 .刘敏,王莉芬,朱杰等.L-选择蛋白可能介导小鼠肝癌细胞经淋巴道转移的研究.解剖学报.35(5):502-506. 2004
8 .刘敏,朱杰,杨佩满等.L-选择蛋白在小鼠肝癌细胞Hca-F和Hca-P的表达及与肿瘤转移潜能的相关性.解剖科学进展.9(2):100-104. 2003
9 . Zamze S, Martinez-Pomares L, Jones H, Taylor PR, Stillion RJ, Gordon S, Wong SY. Recognition of bacterial capsular polysaccharides and lipopolysaccharides by the macrophage mannose receptor. J Biol Chem.2002; 277, 41613–23
1 0 . Luisa MP, Paul R Crocker, Rosangela DS, Nick H, Cristina C, Pauline R, Raymond D, Siamon G. Cell-specific Glycoforms of Sialoadhesin and CD45 Are Counterreceptors for the Cysteine-rich Domain of the Mannose Receptor. The journal of biological chemistry. 1999;274(49):35211–218
1 1 . Su Y, Bakker T, Harris J, Tsang C, Brown GD, Wormald MR, Gordon S, Dwek RA, Rudd PM. Martinez-Pomares L. Glycosylation influences the lectin activities of the macrophage mannose receptor. J Biol Chem.2005, 280, 32811-20
1 2 . Su YR, Tsang C, Bakker T, Harris J, Gordon S, Dwek RA, Martinez-Pomares L,Rudd PM.Glycosylation influences the ligand binding activities of mannose receptor. Adv Exp Med Biol. 2005;564, 25-26
1 3 .刘芯宇.L-选择蛋白与小鼠肝癌细胞Hepa1-6淋巴道转移潜能的相关性.大连医科大学硕士论文
1 4 . Feinberg H et a1.Structure of a C-type carbohydrate recognition domain from the macrophage mannose receptor. J Biol Chem. 2000, 275(28):21539-48
1 5 . McGreal EP, JL Miller, S Gordon. Ligand recognition by antigen-presenting cell C-type lectin receptors. Curr Opin Immunol.2005;17, 18-24
1 6 . Mansour MK, E Latz, S M Levitz. Cryptococcus neoformans glycoantigens are captured by multiple lectin receptors and presented by dendritic cells.J Immunol. 2006;176, 3053-3061
1 7 . Taylor PR, S Gordon, L Martinez-Pomares. The mannose receptor: linking homeostasis and immunity through sugar recognition. Trends Immunol.2005, 26, 104–110
1 8 . Schweizer A, Stahl PD, Rohrer J. A di-aromatic motif in the cytosolic tail of the mannose receptor mediates endosomal sorting.J Biol Chem.2000;275, 29694–700