巨噬细胞移动抑制因子和血管内皮细胞生长因子在类风湿关节炎患者血清中的表达和意义
|
摘要
目的:类风湿关节炎(Rheumatoid Arthritis,RA)是一种原因不明的自身免疫性疾病,以慢性、对称性、进行性多关节炎为主要临床表现。其分布于所有的种族和民族,患者遍及全球,国外统计RA患病率为0.5%～1%。据不完全统计,我国RA的患病率为0.3%～0.5%,男女之比约为1∶3,按此计算,我国大约有450万～600万患者,相当于一个中等城市的总人口,特别值得关注的是,约80%的患者发病年龄在20～45岁,以青壮年居多,造成了各种家庭问题以及巨大的社会负担,这对劳动力的损失,关节严重功能障碍,甚至残疾的情况是不容忽视的。
多方面研究显示RA是一种与环境、细胞、病毒、遗传、性激素及神经精神状态等因素密切相关的疾病。其病理特征是滑膜细胞增生、多种炎性细胞浸润、血管翳形成以及骨和软骨下骨组织的破坏。血管翳形成被认为是RA病理过程的主要环节,而血管新生是产生和维持RA血管翳的主要标志,众多的细胞因子参与了血管新生的调节,近年来,巨噬细胞移动抑制因子(macrophage migration inhibitory factor,MIF)因涉及败血症、肿瘤和自身免疫性疾病的发病机制而成为研究的热点。血管内皮细胞生长因子(vascular endothelial growth factor,VEGF)因直接作用于血管内皮细胞的有丝分裂原,是迄今为止已知的最强的促血管生长因子,在新生血管的形成过程中具有重要的作用。众多研究表明MIF和VEGF作为促血管生成因子在多种肿瘤细胞中高度表达,且与肿瘤的发生、发展及远处转移关系密切。MIF可能通过诱导VEGF的表达而促进肿瘤新生血管的形成和侵袭转移,那么MIF和VEGF在RA发生发展过程中是否也呈协同一致表达,本研究通过酶联免疫吸附实验(ELISA)检测RA患者血清MIF和VEGF的表达水平,分析二者与RA患者临床指标之间的关系,并探讨两者在RA发病机制中的作用。
方法:(1)收集56例来我院就诊的门诊及住院的RA患者,均符合1987年美国风湿病学会(ACR)修订的RA分类诊断标准,根据RA病情活动标准和缓解标准分为RA活动组和RA缓解组;另收集16例骨性关节炎(osteoarthritis,OA)患者作为阴性对照组及15例健康体检者作为正常对照组,各组间年龄、性别构成均无统计学差异。(2)记录入组者相关资料:姓名、性别、年龄、病程、晨僵时间、血沉(ESR)、血小板(PLT)、C-反应蛋白(CRP)、类风湿因子(RF),同时评价患者的关节压痛指数、关节肿胀指数、关节活动痛指数、关节休息痛指数。(3)所有入组者均空腹采肘静脉血3ml,离心后取上清液,置-70℃低温冰箱保存,待实验前在室温下一次解冻。(4)采用酶联免疫吸附法(ELISA)检测入组者血清MIF和VEGF的水平,具体操作步骤和方法严格按试剂盒说明书要求进行,在酶标仪上读取吸光度(A)值,以标准品浓度为横坐标,OD值为纵坐标,绘制标准曲线,计算出各组血清中MIF和VEGF的浓度。(5)应用SPSS13.0统计软件进行统计学分析。
结果:(1) RA患者血清MIF、VEGF水平明显高于OA组(P<0.05)及正常对照组(P<0.01)。(2) RA活动组患者血清MIF、VEGF水平明显高于RA缓解组(P<0.01)。(3)与活动指标的相关性分析:RA活动组患者血清MIF、VEGF表达水平与晨僵时间、ESR、PLT、CRP、关节压痛指数、关节肿胀指数、关节活动痛指数、关节休息痛指数呈正相关(P<0.01),而与年龄、病程、RF无相关性(P>0.05)。(4) RA活动组患者血清MIF与VEGF的表达水平成正相关关系(P<0.01),而在RA缓解组,OA组及正常对照组中血清MIF与VEGF的表达水平无相关性(P>0.05)。
结论:(1) MIF和VEGF在RA患者血清中高水平存在,提示二者参与了RA的发病。(2)联合检测血清MIF和VEGF水平,有助于RA疾病活动性的判断。(3)在RA活动期,血清MIF和VEGF呈协同一致表达,提示MIF可能参与了VEGF的生成。
Objective: Rheumatoid arthritis (RA) is an autoimmune disease of unknown causes, which main clinical manifestation is chronic, symmetry, progressive polyarticular inflammation diseases. The patients of RA are distributed in the worldwide,including all racial and ethnic. Statistics from foreign shown that 0.5 to 1 percent of people has the disease of RA in the worldwide . According to incomplete statistics, 0.3 to 0.5 percent of people has RA in our country,and the ratio of male to female is about 1 to 3. On this basis, it approximately 4.5 million to 6 million patients in our country, which equivalent to a medium-sized cities’total population. In particular, 80 percent of the patients are young adults age of onset of 20 to 45 years, which result in varieties of family issues and a huge social burden. It can not be ignored that the damage of labor force and disability because of severe joint damage and dysfunction.
Many studies have shown that RA is a kind of disease, which has closely related to the environment, cells, viruses, genetics, sex hormones and neuropsychiatric state. The main pathological feature is proliferation of synovial cells, infiltration of inflammatory cell, formation of pannus, damage of bone tissue and cartilage. The pannus formation is recognized as a major segment in the pathogenesis of RA, while angiogenesis is the main symbol of the pannus generation and maintenance in RA. A large number of cytokines play a central role in the regulation of angiogenesis with RA. In recent years, macrophage migration inhibitory factor (MIF) became a research hotspot because of it involved in pathogenesis of sepsis, cancer and autoimmune diseases. Vascular endothelial growth factor (VEGF) was known to be one of the strongest promote blood vessel growth factor which had a direct effect on the vascular endothelial cell mitogen,moreover VEGF play an important role in the formation of new blood vessels. Many studies shown that MIF and VEGF were highly expressed in tumor cells, and the expressions of MIF and VEGF were closely correlated with tumor germination, progression and distant metabasis. MIF may be induced the angiogenesis, invasion and metastasis in tumor via upregulation the expression of VEGF. But their roles have not been known in angiogenesis of RA. We measure the serum MIF and VEGF expression in RA patients by enzyme-linked immunosorbent assay (ELISA), analysis the relationship between the expression of serum MIF, VEGF and the clinical variables of RA, and explore the role of MIF and VEGF in the pathogenesis of RA.
Methods: (1) Collected 56 cases of RA patients, which accorded with the American College of Rheumatology (ACR) 1987 revised criteria for the classification of RA. According to the criteria of diagnosis in RA activities stage and RA remission stage, they were divided into RA active group and RA remission group. 16 cases of osteoarthritis (OA) patients and 15 cases of healthy checkup were used as normal control group. The age, sex composition have no statistical difference in all groups. (2) Recorded the relevant information from all the members before the study: name, sex, age, disease duration, time of morning stiffness, erythrocyte sedimentation rate (ESR), platelet counting (PLT), C-reactive protein (CRP), Rheumatoid factor (RF), joint tenderness index, joint swelling index, joint activity pain index and joint resting pain index. (3) All study members need to draw 3 millilter blood from the vein of elbow in the morning and must be after empty stomach 8 hours, then extracted the liquid supernatant after centrifugation, holded in -70℃low temperature refrigerator, dissolved all the apecimen before the experiment at the common room temperature. (4) The serum level of MIF and VEGF were measured by enzyme-linked immunosorbent assay (ELISA), the steps and methods were strictly accordence with the requirements of kit instructions, read the absorbance (A) values, draw the standard curve which abscissa was the concentration of standard products and the vertical axis was the OD value, then calculated the serum concentrations of MIF and VEGF in all groups. (5) Application SPSS13.0 statistical software for statistical analysis.
Results: (1) The serum level of MIF and VEGF were significantly higher in the RA group than in the OA group (P<0.05) and in the healthy control (P<0.01). (2) The serum level of MIF and VEGF were significantly higher in active group of RA than those in remission group (P<0.01). (3)There were significant correlation between the serum level of MIF,VEGF and the clinical variables of RA disease activity, included ESR,PLT,CRP,joint tenderness index, joint swelling index, joint activity pain index and joint resting pain index (P<0.01). But there were no correlation between the serum level of MIF, VEGF and age, disease duration and RF (P>0.05). (4) The serum level of MIF had good correlation with the serum level of VEGF in active group of RA (P<0.01), while the serum level of MIF and VEGF were no correlation in the remission group of RA,OA group and normal control group (P>0.05).
Conclusions: (1) MIF and VEGF were high level presence in the serum of patients with RA. It was shown that they were involved in the pathogenesis of RA. (2) It contributed to judgment the activity of RA by detecting the serum MIF and VEGF. (3) There was a positive correlation between the serum level of MIF and VEGF in active group of RA. It was shown that MIF may be take part in the generation of VEGF.
多方面研究显示RA是一种与环境、细胞、病毒、遗传、性激素及神经精神状态等因素密切相关的疾病。其病理特征是滑膜细胞增生、多种炎性细胞浸润、血管翳形成以及骨和软骨下骨组织的破坏。血管翳形成被认为是RA病理过程的主要环节,而血管新生是产生和维持RA血管翳的主要标志,众多的细胞因子参与了血管新生的调节,近年来,巨噬细胞移动抑制因子(macrophage migration inhibitory factor,MIF)因涉及败血症、肿瘤和自身免疫性疾病的发病机制而成为研究的热点。血管内皮细胞生长因子(vascular endothelial growth factor,VEGF)因直接作用于血管内皮细胞的有丝分裂原,是迄今为止已知的最强的促血管生长因子,在新生血管的形成过程中具有重要的作用。众多研究表明MIF和VEGF作为促血管生成因子在多种肿瘤细胞中高度表达,且与肿瘤的发生、发展及远处转移关系密切。MIF可能通过诱导VEGF的表达而促进肿瘤新生血管的形成和侵袭转移,那么MIF和VEGF在RA发生发展过程中是否也呈协同一致表达,本研究通过酶联免疫吸附实验(ELISA)检测RA患者血清MIF和VEGF的表达水平,分析二者与RA患者临床指标之间的关系,并探讨两者在RA发病机制中的作用。
方法:(1)收集56例来我院就诊的门诊及住院的RA患者,均符合1987年美国风湿病学会(ACR)修订的RA分类诊断标准,根据RA病情活动标准和缓解标准分为RA活动组和RA缓解组;另收集16例骨性关节炎(osteoarthritis,OA)患者作为阴性对照组及15例健康体检者作为正常对照组,各组间年龄、性别构成均无统计学差异。(2)记录入组者相关资料:姓名、性别、年龄、病程、晨僵时间、血沉(ESR)、血小板(PLT)、C-反应蛋白(CRP)、类风湿因子(RF),同时评价患者的关节压痛指数、关节肿胀指数、关节活动痛指数、关节休息痛指数。(3)所有入组者均空腹采肘静脉血3ml,离心后取上清液,置-70℃低温冰箱保存,待实验前在室温下一次解冻。(4)采用酶联免疫吸附法(ELISA)检测入组者血清MIF和VEGF的水平,具体操作步骤和方法严格按试剂盒说明书要求进行,在酶标仪上读取吸光度(A)值,以标准品浓度为横坐标,OD值为纵坐标,绘制标准曲线,计算出各组血清中MIF和VEGF的浓度。(5)应用SPSS13.0统计软件进行统计学分析。
结果:(1) RA患者血清MIF、VEGF水平明显高于OA组(P<0.05)及正常对照组(P<0.01)。(2) RA活动组患者血清MIF、VEGF水平明显高于RA缓解组(P<0.01)。(3)与活动指标的相关性分析:RA活动组患者血清MIF、VEGF表达水平与晨僵时间、ESR、PLT、CRP、关节压痛指数、关节肿胀指数、关节活动痛指数、关节休息痛指数呈正相关(P<0.01),而与年龄、病程、RF无相关性(P>0.05)。(4) RA活动组患者血清MIF与VEGF的表达水平成正相关关系(P<0.01),而在RA缓解组,OA组及正常对照组中血清MIF与VEGF的表达水平无相关性(P>0.05)。
结论:(1) MIF和VEGF在RA患者血清中高水平存在,提示二者参与了RA的发病。(2)联合检测血清MIF和VEGF水平,有助于RA疾病活动性的判断。(3)在RA活动期,血清MIF和VEGF呈协同一致表达,提示MIF可能参与了VEGF的生成。
Objective: Rheumatoid arthritis (RA) is an autoimmune disease of unknown causes, which main clinical manifestation is chronic, symmetry, progressive polyarticular inflammation diseases. The patients of RA are distributed in the worldwide,including all racial and ethnic. Statistics from foreign shown that 0.5 to 1 percent of people has the disease of RA in the worldwide . According to incomplete statistics, 0.3 to 0.5 percent of people has RA in our country,and the ratio of male to female is about 1 to 3. On this basis, it approximately 4.5 million to 6 million patients in our country, which equivalent to a medium-sized cities’total population. In particular, 80 percent of the patients are young adults age of onset of 20 to 45 years, which result in varieties of family issues and a huge social burden. It can not be ignored that the damage of labor force and disability because of severe joint damage and dysfunction.
Many studies have shown that RA is a kind of disease, which has closely related to the environment, cells, viruses, genetics, sex hormones and neuropsychiatric state. The main pathological feature is proliferation of synovial cells, infiltration of inflammatory cell, formation of pannus, damage of bone tissue and cartilage. The pannus formation is recognized as a major segment in the pathogenesis of RA, while angiogenesis is the main symbol of the pannus generation and maintenance in RA. A large number of cytokines play a central role in the regulation of angiogenesis with RA. In recent years, macrophage migration inhibitory factor (MIF) became a research hotspot because of it involved in pathogenesis of sepsis, cancer and autoimmune diseases. Vascular endothelial growth factor (VEGF) was known to be one of the strongest promote blood vessel growth factor which had a direct effect on the vascular endothelial cell mitogen,moreover VEGF play an important role in the formation of new blood vessels. Many studies shown that MIF and VEGF were highly expressed in tumor cells, and the expressions of MIF and VEGF were closely correlated with tumor germination, progression and distant metabasis. MIF may be induced the angiogenesis, invasion and metastasis in tumor via upregulation the expression of VEGF. But their roles have not been known in angiogenesis of RA. We measure the serum MIF and VEGF expression in RA patients by enzyme-linked immunosorbent assay (ELISA), analysis the relationship between the expression of serum MIF, VEGF and the clinical variables of RA, and explore the role of MIF and VEGF in the pathogenesis of RA.
Methods: (1) Collected 56 cases of RA patients, which accorded with the American College of Rheumatology (ACR) 1987 revised criteria for the classification of RA. According to the criteria of diagnosis in RA activities stage and RA remission stage, they were divided into RA active group and RA remission group. 16 cases of osteoarthritis (OA) patients and 15 cases of healthy checkup were used as normal control group. The age, sex composition have no statistical difference in all groups. (2) Recorded the relevant information from all the members before the study: name, sex, age, disease duration, time of morning stiffness, erythrocyte sedimentation rate (ESR), platelet counting (PLT), C-reactive protein (CRP), Rheumatoid factor (RF), joint tenderness index, joint swelling index, joint activity pain index and joint resting pain index. (3) All study members need to draw 3 millilter blood from the vein of elbow in the morning and must be after empty stomach 8 hours, then extracted the liquid supernatant after centrifugation, holded in -70℃low temperature refrigerator, dissolved all the apecimen before the experiment at the common room temperature. (4) The serum level of MIF and VEGF were measured by enzyme-linked immunosorbent assay (ELISA), the steps and methods were strictly accordence with the requirements of kit instructions, read the absorbance (A) values, draw the standard curve which abscissa was the concentration of standard products and the vertical axis was the OD value, then calculated the serum concentrations of MIF and VEGF in all groups. (5) Application SPSS13.0 statistical software for statistical analysis.
Results: (1) The serum level of MIF and VEGF were significantly higher in the RA group than in the OA group (P<0.05) and in the healthy control (P<0.01). (2) The serum level of MIF and VEGF were significantly higher in active group of RA than those in remission group (P<0.01). (3)There were significant correlation between the serum level of MIF,VEGF and the clinical variables of RA disease activity, included ESR,PLT,CRP,joint tenderness index, joint swelling index, joint activity pain index and joint resting pain index (P<0.01). But there were no correlation between the serum level of MIF, VEGF and age, disease duration and RF (P>0.05). (4) The serum level of MIF had good correlation with the serum level of VEGF in active group of RA (P<0.01), while the serum level of MIF and VEGF were no correlation in the remission group of RA,OA group and normal control group (P>0.05).
Conclusions: (1) MIF and VEGF were high level presence in the serum of patients with RA. It was shown that they were involved in the pathogenesis of RA. (2) It contributed to judgment the activity of RA by detecting the serum MIF and VEGF. (3) There was a positive correlation between the serum level of MIF and VEGF in active group of RA. It was shown that MIF may be take part in the generation of VEGF.
引文
1 Mitchell RA.Mechanisms and effectors of MIF-dependent promotion of tumourigenesis.Cell Signal,2004,16(1):13-19
2 Flaster H,Bernhagen J,Calandra T,et al.The macrophage migration inhibitory factor glucocorticoid dyad: regulation of inflammation and immunity.Mol Endocrinol,2007,21(6):1267-1280
3 Scola MP,Imagawa T,Boivin GP,et al.Expression of angiogenic factors in juvenile rheumatoid arthritis:Correlation with revascularization of human synovium engrafted into SCID mice.Arthritis Rheum,2001,44(14):794-801
4 O’Connor DS,Schechner JS,Adida C,et al.Control of apoptesis during angiogesis by surviving expression in endothelial cells.Am J Pathol,2000,156(5):393-402
5 Leng L,Metz CN,Fang Y,et al.MIF signal transduction initiated by binding to CD74.J Exp Med,2003,197(11):1467-1476
6 Kleamann R,Hausser A,Geiger G,et al.Intracellular action of the cytokineMIF to modulate AP-1 activity and the cell cycle through Jab1.Nature,2000,408(6809):211-216
7 Li Y,Lu C,Xing G,et al.Macrophage Migration inhibitory factor directly interact swith hepatopoietin and regulates the proliferation of hepatoma Cell.Exp Cell Res,2004,300(2):379-387
8 Roger T,Dav IDJ,Glause MP,et al.MIF regulates innate immune responses through modulation of Toll-like receptor4. Nature,2001,414(6866):920-924
9 Calandra T,Roger T.Macrophage migration inhibitory factor:a regulator of innate immunity.Nat Rev Immunol,2003,3(10):791-800
10 Morand EF,Leech M.Macrophage migration inhibitory factor in rheumatoid arthritis.Front Biosei,2005,10(1):12-22
11 Sampey Annaleise V,Hall Pamela H,Mitchell Robert A,et a1.Regulation of synoviocyte phospholipase A2 and cyclooxygenase 2 by macrophage migration inhibitory factor.Arthritis Rheum,2001,44(17):1273-1280
12 Onodera S,Nishihira J,Koyama Y,et a1.Macrophage migration inhibitory factor up-regulates the expression of interleukln-8 messenger RNA in synovial fibroblasts of rheumatoid arthritis patients-Common transcriptional regulatory mechanism between interleukin-8 and interleukin-l beta.Arthritis Rheum,2004,50(23):1437-1447
13 Mitchell RA,Liao H,Chesney J,et al.Macrophagemigration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53:regulatory role in the innate immune response.Proc Natl Acad Sci USA,2002,99(1):345-351
14 Leech M,Lacey D,Rongxue J,et al.Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis. Arthritis Rheum,2003,48(7):1881-1889
15 Onodera S,Tanji H,Suzuki K,et al.High expression of MIF in the synovial tissues of Rheumatoid joints.Cytokine 1999,11(2):163-167
16 Lacey D,Sovmpey A,Mitchell R,et al.Control of fibroblas t-likesynoviocyte proliferation by macrophage migration inhibitory factor.Arthritis Rheum 2003,48(1):103-109
17 Onodera S,Kaneda K,Mizue Y,et al.Macrophage migration inhibitory factor upregulates expression of matrix metallop roteinases in synovial fibroblasts of rheumatoid arthritis.J Biol Chem,2000,275(1):444-450
18 Pakozdi A,Amin MA,Haas CS,et al.Macrophase migration inhibitory factor:a mediator of matrix metalloproteinase-2 production in rheumatoid arthritis.Arthritis Res Ther,2006,8(4):132-138
19 Szekanece Z,Alisa EK.Macrophage and their products in rheumatoid arthritis.CurrOpin Rheum atol,2007,19(3):289-295
20 Onodera S,Nishihira J,Wabuchi K,et a1.Macrophage migration inhibitory factor upregulates matrix metalloproteinase-9 and-13 inratosteoblasts-Relevance to intracellular signaling pathways.J Biol Chem,2002,277:7865-7874
21 Leech M,Metz C,Hall P,et al.Macrophage migration inhibitory factor in rheumatoid arthtitis.Arthritis Rheum 1999,42(8):1601-1608
22 Morand EF,Leech M,Wedon H,et al.Macrophage migration inhibitory factor in rheumatoid arthritis:clinical correlations.Rheumatology,2002,41(5):558-562
23 Kim HR,Park MK,Cho ML,et al.Macrophage migration inhibitory factor upregulates angiogenic factors and correlates with clinical measures in rheumatoid arthtitis.J Rheumatol,2007,34(5),927-936
24 Tammela T,Enholm B,Alitalo K,et al.The biology of vascular endothelial growth factors. Cardiovasc Res,2005,65 (3):550-563
25 Dor JE,Christensen I,Mooney DJ.Vascular endothelial growth factor(VEGF) hediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am J Pathol,1999,154(8):375-383
26 Giatromanolaki A,Sivridis E,Athanassou N,et al.The angiogenic Pathway“vascular endothelial growth factor/flk-1 (KDR)-recrpor”in rheumatoid arthritis and osteoarthritis.J Pathol 2001,194 (1):101-107
27景红,吴江.缺氧诱导因子-1α和血管内皮生长因子在结直肠癌组织中的表达及意义.山东医药,2003,43(34):12-14
28 Mde Bandt M,Ben Mahdi MH,Ollivier V,et al.Blockade of vascular endothelial growth factor receptorⅠ(VEGF RⅠ),but not VEGF-R Ⅱ,suppresses joint destruction in the K/BxN model of rheumatoid arthritis.J Immunol,2003,171(9):4853-4859
29 Fava RA,Olsen NJ,Spencer-Green G,et al.Vascular permeability factor/endothelial growth factor(VPF/VEGF):accumulation and expression in human synovial fluids and rheumatoid synovial tissue.J Exp Med,1994,180(1):341-346
30 Ballara S,Taylor PC,Reusch P,et al.Raised serum vascular endot helial growth factor levels are associated with destructive change in inflammatory arthritis.Arthritis Rheum,2001,44(9):2055-2064
31 Zacharski LR,Brown FE,Mermoli VA,et al.Pathways of coagulation activation in situ in rheumatoid synovial tissue.Clin Immunol Immunopathol,1992,63(2):155-162
32 Giatromanolaki A,Sivridis E,Maltezos E,et al.Upregulated hypoxia inducible factor-1 alpha and -2 alpha pathway in rheumatoid arthritis and osteoarthritis.Arthritis Res Ther, 2003,5 (4):193-201
33 Weinberg JB,Pippen AM,Greenberg CS.Extravascular fibrin formation and dissolution in synovial tissue of patients with osteoarthritis and rheumatoid arthritis.Arthritis Rheum,1991,34(8):996-1005
34 Sone H ,Sakauchi M,Takahashi A,et al.Elevated levels of vascular endothelial growth factor in the sera of patients with rheumatoid arthritis.Correlation with disease activity.J Life Sci,2001,69(16):1861-1869
35 Hashimoto N,Iwasaki T,Kitano M,et al.Levels of vascular endothelial growth factor and hepatocyte growth factor in sera of patients with rheumatic diseases.Mod Rheumatol,2003,13(2):129-134
36李长有,解克非,葛瑞等.VEGF在类风湿关节炎病人骨小梁成骨细胞中的表达及意义.中国医科大学学报,2008,37(4),534-536
37 Brahn E,Banquerigo ML,Lee JK,et al.An angiogenesis inhibitor,2-methoxyestradiol,involutes rat collagen-induced arthritis and suppresses gene expression of synovial endothelial growth factor and basic fibroblast growth factor.J Rheumatol.2008,35(11),2119-2128
38鲁静,侯平.关节炎小鼠关节组织提取物对内皮细胞增殖影响及mVEGF的关系.中国免疫学杂志,2002,16(6):383-385
39 Yang Y,Degranpre P,Kharfi A, et al.Identification of macrophage migration inhibitory factor as a potent endothelial cell growth promoting agent released by ectopic human endometrial cells.J Clin Endocrinol Metab,2000,85(12):721-727
40 Del Vecchio MT,Tripodi SA,Arcuri F,et al.Macrophage migration inhibitory factor in prostatic adenocarcinoma:correlation with tumor grading and combination endocrine treatment related changes.Prostate,2000,45(1):51-57
1 Donn R,Alourfi Z,De Benedetti F,et a1.Mutation screening of the macrophage migration inhibitory factor gene:positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis.Arthritis Rheum,2002,46(9):2402-2409
2 Leng L,Meta CN,Fang Y,et al.MIF signal transduction initiated by bindingto CD74.Exp Med,2003,197(11):1467-1476
3陈伟英,李广然,方芳等.外周血单个核细胞巨噬细胞移动抑制因子表达及其与狼疮活动.中华内科杂志,2004,43(8):572-575
4 Brown FG,Nikolic-Paterson DJ,Hill PA,et al.Urine macrophage migration inhibitory factor reflects the severity of renal injury in human glumerulonephritis.J Am Soc Nephrol,2002,13(1):7-13
5 Hoi AY,Hickey MJ,Hall P,et al.Macrophage migration inhibitory factor deficiency attenuates macrophage recruitment,glomerulonephritis,and lethality in MRL/lpr mice.Immunol,2006,177(8):5687-5696
6陈伟英,李广然,余学清等.尿巨噬细胞移动抑制因子浓度与狼疮肾肾组织损害的关系.中华肾脏病杂志,2004,20(2):83-86
7 Morand EF,Leech M.Macrophage migration inhibitory factor in rheumatoid arthritis.Front Biosei,2005,1(10):12-22
8 Baumann R,Casaulta C,Simon D,et a1.Macrophage migration inhibitory factor delays apoptosis in neutrophils by inhibiting the mitochondria-dependent death pathway.Faseb J,2003,17(15):2221-2230
9 Onodera S,Nishihira J,Wabuchi K,et a1.Macrophage migration inhibitory factor upregulates matrix metalloproteinase-9 and -13 in rat osteoblasts-Relevance to intracellular signaling pathways.Biol Chem,2002,277(10):7865-7874
10 Pakozdi A,Amin M,Haas C,et a1.Macrophase migration inhibitory factor:a mediator of matrix metalloproteinase-2 production in rheumatoid arthritis.Arthritis Research Therapy,2006,8(4):1186-2021
11 Mikulowska A, Metz CN,Bucala R. Macrophage migration inhibitory factor is involved in the pathogenesis of collagen type II-induced arthritis in mice.Immunol,1997,158(11):5514-5517
12 Ichiyama H,Onodera S,Nishihira J,et al.Inhibition of joint inflammation and destruction induced by anti-typeⅡcollagen antibody/lipopolysaccharide (LPS)-induced arthritis in mice due to deletion of macrophage migration inhibitory factor(MIF).Cytokine,2004,26(5):187-194
13 Santos L,Hall P,Metz C,et al.Role of macrophage migration inhibitory factor (MIF) in murine antigen-induced arthritis: interaction with glucocorticoids.Clin Exp Immunol,2001,123(2):309-314
14 Morand EF,Leech M,Weedon H,et al.Macrophage migration inhibitory factor in rheumatoid arthritis:clinical correlations.Rheumatology,2002,41(5):558-5621
15 Radstake TR,Sweep FC,Welsing P,et al. Correlation of rheumatoid arthritis severity with the genetic functional variants and circulating levels of macrophage migration inhibitory factor.Arthritis Rheum,2005,52(10):3020-3029
16 De Benedetti F,Meazza C,Vivarelli M,et al.Functional and prognostic relevance of the -173 polymorphism of the macrophage migration inhibitory factor gene in systemic-onset juvenile idiopathic arthritis.Arthritis Rheum,2003,48(5):1398-1407
17 Selvi E,Tripodi SA,Catenaccio M,et al.Expression of macrophage migration inhibitory factor in diffuse systemic sclerosis.Ann Rheum Dis,2003,62(5):460-464
18 Kim JY,Kwok SK,Hur KH,et al.Up-regulated macrophage migration inhibitory factor protects apoptosis of dermal fibroblasts in patients with systemic sclerosis.Clin Exp Immunol,2008,152(2):328-335
19 Leung JC,Chan LY,Tsang AW,et al.Anti-macrophage migration inhibitory factor reduces transforming growth factor-beta 1 expression in experimental IgA nephropathy.Nephrol Dial Transplant,2004,19(8):1976-1985
20 Wu SP,Leng L,Feng Z,et al.Macrophage Migration Inhibitory Factor Promoter Polymorphisms and the Clinical Expression of Scleroderma.Arthritis Rheum,2006,54(11):3661-3669
21 Becker H,Willeke P,Schotte H.Macrophage migration inhibitory factor may contribute to vasculopathy in systemic sclerosis.Clin Rheumatol,2008,27(10):1307-1311
22 Willeke P,Gaubitz M,Schotte H,et al.Increased serum levels ofmacrophage migration inhibitory factor in patients with primary Sj?gren's syndrome.Arthritis Research Therapy,2007,9(43):1186-1193
23 Beswick EJ,Pinchuk IV,Suarez G,et al.Helicobacter pylori CagA-dependent macrophage migration inhibitory factor produced by gastric epithelial cells binds to CD74 and stimulates procarcinogenic events.J Immunol 2006,176(11):6794-6801
24 Talos F,Mena P,Fingerle-Rowson G,et al.MIF loss impairs Myc-induced lymphomagenesis.Cell Death Differ,2005,12(10):1319-1328
25 Becker H,Maaser C,Mickholz E,et al. Relationship between serum levels of macrophage migration inhibitory factor and the activity of antineutrophil cytoplasmic antibody-associated vasculitides. Clin Rheumatol,2006,25(3):368-372
26 Zou YQ,Lu LJ,Li SJ,et al.The levels of macrophage migration inhibitory factor as an indicator of disease activity and severity in adult-onset Still's disease.Clin Biochem,2008,41(7):519-524
27 Onodera S,Ohshima S,Tohyama H,et a1.A novel DNA vaccine targeting macrophage migration inhibitory factor protects joints from intlarmnation and destruction in murine models of arthritis.Arthritis Rheum,2007,56(2):52l-530
2 Flaster H,Bernhagen J,Calandra T,et al.The macrophage migration inhibitory factor glucocorticoid dyad: regulation of inflammation and immunity.Mol Endocrinol,2007,21(6):1267-1280
3 Scola MP,Imagawa T,Boivin GP,et al.Expression of angiogenic factors in juvenile rheumatoid arthritis:Correlation with revascularization of human synovium engrafted into SCID mice.Arthritis Rheum,2001,44(14):794-801
4 O’Connor DS,Schechner JS,Adida C,et al.Control of apoptesis during angiogesis by surviving expression in endothelial cells.Am J Pathol,2000,156(5):393-402
5 Leng L,Metz CN,Fang Y,et al.MIF signal transduction initiated by binding to CD74.J Exp Med,2003,197(11):1467-1476
6 Kleamann R,Hausser A,Geiger G,et al.Intracellular action of the cytokineMIF to modulate AP-1 activity and the cell cycle through Jab1.Nature,2000,408(6809):211-216
7 Li Y,Lu C,Xing G,et al.Macrophage Migration inhibitory factor directly interact swith hepatopoietin and regulates the proliferation of hepatoma Cell.Exp Cell Res,2004,300(2):379-387
8 Roger T,Dav IDJ,Glause MP,et al.MIF regulates innate immune responses through modulation of Toll-like receptor4. Nature,2001,414(6866):920-924
9 Calandra T,Roger T.Macrophage migration inhibitory factor:a regulator of innate immunity.Nat Rev Immunol,2003,3(10):791-800
10 Morand EF,Leech M.Macrophage migration inhibitory factor in rheumatoid arthritis.Front Biosei,2005,10(1):12-22
11 Sampey Annaleise V,Hall Pamela H,Mitchell Robert A,et a1.Regulation of synoviocyte phospholipase A2 and cyclooxygenase 2 by macrophage migration inhibitory factor.Arthritis Rheum,2001,44(17):1273-1280
12 Onodera S,Nishihira J,Koyama Y,et a1.Macrophage migration inhibitory factor up-regulates the expression of interleukln-8 messenger RNA in synovial fibroblasts of rheumatoid arthritis patients-Common transcriptional regulatory mechanism between interleukin-8 and interleukin-l beta.Arthritis Rheum,2004,50(23):1437-1447
13 Mitchell RA,Liao H,Chesney J,et al.Macrophagemigration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53:regulatory role in the innate immune response.Proc Natl Acad Sci USA,2002,99(1):345-351
14 Leech M,Lacey D,Rongxue J,et al.Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis. Arthritis Rheum,2003,48(7):1881-1889
15 Onodera S,Tanji H,Suzuki K,et al.High expression of MIF in the synovial tissues of Rheumatoid joints.Cytokine 1999,11(2):163-167
16 Lacey D,Sovmpey A,Mitchell R,et al.Control of fibroblas t-likesynoviocyte proliferation by macrophage migration inhibitory factor.Arthritis Rheum 2003,48(1):103-109
17 Onodera S,Kaneda K,Mizue Y,et al.Macrophage migration inhibitory factor upregulates expression of matrix metallop roteinases in synovial fibroblasts of rheumatoid arthritis.J Biol Chem,2000,275(1):444-450
18 Pakozdi A,Amin MA,Haas CS,et al.Macrophase migration inhibitory factor:a mediator of matrix metalloproteinase-2 production in rheumatoid arthritis.Arthritis Res Ther,2006,8(4):132-138
19 Szekanece Z,Alisa EK.Macrophage and their products in rheumatoid arthritis.CurrOpin Rheum atol,2007,19(3):289-295
20 Onodera S,Nishihira J,Wabuchi K,et a1.Macrophage migration inhibitory factor upregulates matrix metalloproteinase-9 and-13 inratosteoblasts-Relevance to intracellular signaling pathways.J Biol Chem,2002,277:7865-7874
21 Leech M,Metz C,Hall P,et al.Macrophage migration inhibitory factor in rheumatoid arthtitis.Arthritis Rheum 1999,42(8):1601-1608
22 Morand EF,Leech M,Wedon H,et al.Macrophage migration inhibitory factor in rheumatoid arthritis:clinical correlations.Rheumatology,2002,41(5):558-562
23 Kim HR,Park MK,Cho ML,et al.Macrophage migration inhibitory factor upregulates angiogenic factors and correlates with clinical measures in rheumatoid arthtitis.J Rheumatol,2007,34(5),927-936
24 Tammela T,Enholm B,Alitalo K,et al.The biology of vascular endothelial growth factors. Cardiovasc Res,2005,65 (3):550-563
25 Dor JE,Christensen I,Mooney DJ.Vascular endothelial growth factor(VEGF) hediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am J Pathol,1999,154(8):375-383
26 Giatromanolaki A,Sivridis E,Athanassou N,et al.The angiogenic Pathway“vascular endothelial growth factor/flk-1 (KDR)-recrpor”in rheumatoid arthritis and osteoarthritis.J Pathol 2001,194 (1):101-107
27景红,吴江.缺氧诱导因子-1α和血管内皮生长因子在结直肠癌组织中的表达及意义.山东医药,2003,43(34):12-14
28 Mde Bandt M,Ben Mahdi MH,Ollivier V,et al.Blockade of vascular endothelial growth factor receptorⅠ(VEGF RⅠ),but not VEGF-R Ⅱ,suppresses joint destruction in the K/BxN model of rheumatoid arthritis.J Immunol,2003,171(9):4853-4859
29 Fava RA,Olsen NJ,Spencer-Green G,et al.Vascular permeability factor/endothelial growth factor(VPF/VEGF):accumulation and expression in human synovial fluids and rheumatoid synovial tissue.J Exp Med,1994,180(1):341-346
30 Ballara S,Taylor PC,Reusch P,et al.Raised serum vascular endot helial growth factor levels are associated with destructive change in inflammatory arthritis.Arthritis Rheum,2001,44(9):2055-2064
31 Zacharski LR,Brown FE,Mermoli VA,et al.Pathways of coagulation activation in situ in rheumatoid synovial tissue.Clin Immunol Immunopathol,1992,63(2):155-162
32 Giatromanolaki A,Sivridis E,Maltezos E,et al.Upregulated hypoxia inducible factor-1 alpha and -2 alpha pathway in rheumatoid arthritis and osteoarthritis.Arthritis Res Ther, 2003,5 (4):193-201
33 Weinberg JB,Pippen AM,Greenberg CS.Extravascular fibrin formation and dissolution in synovial tissue of patients with osteoarthritis and rheumatoid arthritis.Arthritis Rheum,1991,34(8):996-1005
34 Sone H ,Sakauchi M,Takahashi A,et al.Elevated levels of vascular endothelial growth factor in the sera of patients with rheumatoid arthritis.Correlation with disease activity.J Life Sci,2001,69(16):1861-1869
35 Hashimoto N,Iwasaki T,Kitano M,et al.Levels of vascular endothelial growth factor and hepatocyte growth factor in sera of patients with rheumatic diseases.Mod Rheumatol,2003,13(2):129-134
36李长有,解克非,葛瑞等.VEGF在类风湿关节炎病人骨小梁成骨细胞中的表达及意义.中国医科大学学报,2008,37(4),534-536
37 Brahn E,Banquerigo ML,Lee JK,et al.An angiogenesis inhibitor,2-methoxyestradiol,involutes rat collagen-induced arthritis and suppresses gene expression of synovial endothelial growth factor and basic fibroblast growth factor.J Rheumatol.2008,35(11),2119-2128
38鲁静,侯平.关节炎小鼠关节组织提取物对内皮细胞增殖影响及mVEGF的关系.中国免疫学杂志,2002,16(6):383-385
39 Yang Y,Degranpre P,Kharfi A, et al.Identification of macrophage migration inhibitory factor as a potent endothelial cell growth promoting agent released by ectopic human endometrial cells.J Clin Endocrinol Metab,2000,85(12):721-727
40 Del Vecchio MT,Tripodi SA,Arcuri F,et al.Macrophage migration inhibitory factor in prostatic adenocarcinoma:correlation with tumor grading and combination endocrine treatment related changes.Prostate,2000,45(1):51-57
1 Donn R,Alourfi Z,De Benedetti F,et a1.Mutation screening of the macrophage migration inhibitory factor gene:positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis.Arthritis Rheum,2002,46(9):2402-2409
2 Leng L,Meta CN,Fang Y,et al.MIF signal transduction initiated by bindingto CD74.Exp Med,2003,197(11):1467-1476
3陈伟英,李广然,方芳等.外周血单个核细胞巨噬细胞移动抑制因子表达及其与狼疮活动.中华内科杂志,2004,43(8):572-575
4 Brown FG,Nikolic-Paterson DJ,Hill PA,et al.Urine macrophage migration inhibitory factor reflects the severity of renal injury in human glumerulonephritis.J Am Soc Nephrol,2002,13(1):7-13
5 Hoi AY,Hickey MJ,Hall P,et al.Macrophage migration inhibitory factor deficiency attenuates macrophage recruitment,glomerulonephritis,and lethality in MRL/lpr mice.Immunol,2006,177(8):5687-5696
6陈伟英,李广然,余学清等.尿巨噬细胞移动抑制因子浓度与狼疮肾肾组织损害的关系.中华肾脏病杂志,2004,20(2):83-86
7 Morand EF,Leech M.Macrophage migration inhibitory factor in rheumatoid arthritis.Front Biosei,2005,1(10):12-22
8 Baumann R,Casaulta C,Simon D,et a1.Macrophage migration inhibitory factor delays apoptosis in neutrophils by inhibiting the mitochondria-dependent death pathway.Faseb J,2003,17(15):2221-2230
9 Onodera S,Nishihira J,Wabuchi K,et a1.Macrophage migration inhibitory factor upregulates matrix metalloproteinase-9 and -13 in rat osteoblasts-Relevance to intracellular signaling pathways.Biol Chem,2002,277(10):7865-7874
10 Pakozdi A,Amin M,Haas C,et a1.Macrophase migration inhibitory factor:a mediator of matrix metalloproteinase-2 production in rheumatoid arthritis.Arthritis Research Therapy,2006,8(4):1186-2021
11 Mikulowska A, Metz CN,Bucala R. Macrophage migration inhibitory factor is involved in the pathogenesis of collagen type II-induced arthritis in mice.Immunol,1997,158(11):5514-5517
12 Ichiyama H,Onodera S,Nishihira J,et al.Inhibition of joint inflammation and destruction induced by anti-typeⅡcollagen antibody/lipopolysaccharide (LPS)-induced arthritis in mice due to deletion of macrophage migration inhibitory factor(MIF).Cytokine,2004,26(5):187-194
13 Santos L,Hall P,Metz C,et al.Role of macrophage migration inhibitory factor (MIF) in murine antigen-induced arthritis: interaction with glucocorticoids.Clin Exp Immunol,2001,123(2):309-314
14 Morand EF,Leech M,Weedon H,et al.Macrophage migration inhibitory factor in rheumatoid arthritis:clinical correlations.Rheumatology,2002,41(5):558-5621
15 Radstake TR,Sweep FC,Welsing P,et al. Correlation of rheumatoid arthritis severity with the genetic functional variants and circulating levels of macrophage migration inhibitory factor.Arthritis Rheum,2005,52(10):3020-3029
16 De Benedetti F,Meazza C,Vivarelli M,et al.Functional and prognostic relevance of the -173 polymorphism of the macrophage migration inhibitory factor gene in systemic-onset juvenile idiopathic arthritis.Arthritis Rheum,2003,48(5):1398-1407
17 Selvi E,Tripodi SA,Catenaccio M,et al.Expression of macrophage migration inhibitory factor in diffuse systemic sclerosis.Ann Rheum Dis,2003,62(5):460-464
18 Kim JY,Kwok SK,Hur KH,et al.Up-regulated macrophage migration inhibitory factor protects apoptosis of dermal fibroblasts in patients with systemic sclerosis.Clin Exp Immunol,2008,152(2):328-335
19 Leung JC,Chan LY,Tsang AW,et al.Anti-macrophage migration inhibitory factor reduces transforming growth factor-beta 1 expression in experimental IgA nephropathy.Nephrol Dial Transplant,2004,19(8):1976-1985
20 Wu SP,Leng L,Feng Z,et al.Macrophage Migration Inhibitory Factor Promoter Polymorphisms and the Clinical Expression of Scleroderma.Arthritis Rheum,2006,54(11):3661-3669
21 Becker H,Willeke P,Schotte H.Macrophage migration inhibitory factor may contribute to vasculopathy in systemic sclerosis.Clin Rheumatol,2008,27(10):1307-1311
22 Willeke P,Gaubitz M,Schotte H,et al.Increased serum levels ofmacrophage migration inhibitory factor in patients with primary Sj?gren's syndrome.Arthritis Research Therapy,2007,9(43):1186-1193
23 Beswick EJ,Pinchuk IV,Suarez G,et al.Helicobacter pylori CagA-dependent macrophage migration inhibitory factor produced by gastric epithelial cells binds to CD74 and stimulates procarcinogenic events.J Immunol 2006,176(11):6794-6801
24 Talos F,Mena P,Fingerle-Rowson G,et al.MIF loss impairs Myc-induced lymphomagenesis.Cell Death Differ,2005,12(10):1319-1328
25 Becker H,Maaser C,Mickholz E,et al. Relationship between serum levels of macrophage migration inhibitory factor and the activity of antineutrophil cytoplasmic antibody-associated vasculitides. Clin Rheumatol,2006,25(3):368-372
26 Zou YQ,Lu LJ,Li SJ,et al.The levels of macrophage migration inhibitory factor as an indicator of disease activity and severity in adult-onset Still's disease.Clin Biochem,2008,41(7):519-524
27 Onodera S,Ohshima S,Tohyama H,et a1.A novel DNA vaccine targeting macrophage migration inhibitory factor protects joints from intlarmnation and destruction in murine models of arthritis.Arthritis Rheum,2007,56(2):52l-530