系统性红斑狼疮患者TH2型细胞因子受体表达及其基因多态性的研究
摘要
目的 初步研究三种Th2型细胞因子受体(IL-4R，IL-6R，IL-10R)在系统性红斑狼疮(SLE)发病机制中的作用及其潜在的临床意义，并探讨部分Th1和Th2型细胞因子受体基因多态性与SLE疾病易感性的关系。
方法 应用逆转录-聚合酶链反应(RT-PCR)检测89例SLE患者和30例健康对照者外周血单一核细胞(PBMC)的IL-4R、IL-6R和IL-10R mRNA的表达水平；用ELISA法检测受试者血清中IL-4、IL-6和IL-10水平。采用聚合酶链反应—单链构象多态性(PCR-SSCP)、聚合酶链反应限制性片段长度多态性(PCR-RFLP)和DNA测序方法进行IL-4R，IL-10R和IFNγR的基因多态性分析。
结果 Ⅰ．①活动期SLE患者、非活动期SLE患者及健康对照者IL-4R、IL-6R和IL-10R表达阳性率为100％。②PBMC的IL-4RmRNA表达水平：活动期SLE患者(1组)为0.60±0.147，非活动期SLE患者(2组)为0.40±0.13，健康对照者(3组)为0.37±0.07；1组和2组间比较有显著性差异(P＜0.05)，1组和3组间比较有显著性差异(P＜0.05)，2组和3组间比较无显著性差异(P＞0.05)。PBMC的IL-6RmRNA表达水平：1组为0.90±0.27，2组为0.52±0.11，3组为0.57±0.24；1组和2组间比较有显著性差异(P＜0.05)，1组和3组间比较有显著性差异(P＜0.05)，2组和3组间比较无显著性差异(P＞0.05)。PBMC的IL-10RmRNA表达水平：1组为0.87±0.29，2组为0.72±0.21，3组为0.68±0.14；1组和2组间比较有显著性差异(P＜0.05)，1组和3组间比较有显著性差异(P＜0.05)，2组和3组间比较无显著性差异(P＞0.05)。SLE患者外周血PBMC的IL-4R、IL-6R和IL-10R mRNA的表达量与SLEDAI积分呈正相关性，具有统计学意义(r值分别为0.500、0.421和0.244，P值均小于0.05)。
Objective To investigate the roles of Th2 cytokine receptors in the pathogenesis of systemic lupus erythematosus (SLE). To assess the correlation between the polymorphisms of some Th2 /Th1 cytokine receptor genes and susceptibility of SLE in Chinese Han nationality.
Methods RT-PCR technique was used to semiquantititively analyze the mRNA expression of IL-4R, IL-6R and IL-10R in PBMC from 89 patients with SLE and 30 healthy controls. Double antibody sandwich ELISA was applied to determine the serum levels of three Th2 cytokines. Genotypes of IL4RA, IL10RA and IFNGR were examined by the reverse transcription-polymerase chain reaction (RT-PCR), single-strand conformation polymorphism (SSCP), restriction fragment length polymorphism (RFLP) method and DNA sequencing.
Results The mRNA expression of Th2 cytokine receptors was positively detected in 100% of subjects, including active SLE group(group Ⅰ), inactive SLE group(group Ⅱ) and healthy control group(groupⅢ). The mean level of IL-4R mRNA expression in group Ⅰ , Ⅱ or Ⅲ was 0.604±0.147, 0.40±0.13 or 0.37±0.07, respectively. Compared with group Ⅱ or group Ⅲ, the mean level of IL-4R mRNA expressions was markedly increased in group Ⅰ (P<0.05), with non-statistical difference between group Ⅱ and groupⅢ (P=0.315). The mean level of IL-6R mRNA expressions in group I , II or III was 0.902±0.273, 0.519±0.11 or 0.573±0.24, respectively. Compared with group Ⅱ or group Ⅲ, the mean level of IL-6R mRNA expression in group Ⅰ was markedly increased (P<0.05), with non-statistical difference between group Ⅱ and group Ⅲ (P=0.289). The mean levels of IL-IOR mRNA expression in
方法 应用逆转录-聚合酶链反应(RT-PCR)检测89例SLE患者和30例健康对照者外周血单一核细胞(PBMC)的IL-4R、IL-6R和IL-10R mRNA的表达水平；用ELISA法检测受试者血清中IL-4、IL-6和IL-10水平。采用聚合酶链反应—单链构象多态性(PCR-SSCP)、聚合酶链反应限制性片段长度多态性(PCR-RFLP)和DNA测序方法进行IL-4R，IL-10R和IFNγR的基因多态性分析。
结果 Ⅰ．①活动期SLE患者、非活动期SLE患者及健康对照者IL-4R、IL-6R和IL-10R表达阳性率为100％。②PBMC的IL-4RmRNA表达水平：活动期SLE患者(1组)为0.60±0.147，非活动期SLE患者(2组)为0.40±0.13，健康对照者(3组)为0.37±0.07；1组和2组间比较有显著性差异(P＜0.05)，1组和3组间比较有显著性差异(P＜0.05)，2组和3组间比较无显著性差异(P＞0.05)。PBMC的IL-6RmRNA表达水平：1组为0.90±0.27，2组为0.52±0.11，3组为0.57±0.24；1组和2组间比较有显著性差异(P＜0.05)，1组和3组间比较有显著性差异(P＜0.05)，2组和3组间比较无显著性差异(P＞0.05)。PBMC的IL-10RmRNA表达水平：1组为0.87±0.29，2组为0.72±0.21，3组为0.68±0.14；1组和2组间比较有显著性差异(P＜0.05)，1组和3组间比较有显著性差异(P＜0.05)，2组和3组间比较无显著性差异(P＞0.05)。SLE患者外周血PBMC的IL-4R、IL-6R和IL-10R mRNA的表达量与SLEDAI积分呈正相关性，具有统计学意义(r值分别为0.500、0.421和0.244，P值均小于0.05)。
Objective To investigate the roles of Th2 cytokine receptors in the pathogenesis of systemic lupus erythematosus (SLE). To assess the correlation between the polymorphisms of some Th2 /Th1 cytokine receptor genes and susceptibility of SLE in Chinese Han nationality.
Methods RT-PCR technique was used to semiquantititively analyze the mRNA expression of IL-4R, IL-6R and IL-10R in PBMC from 89 patients with SLE and 30 healthy controls. Double antibody sandwich ELISA was applied to determine the serum levels of three Th2 cytokines. Genotypes of IL4RA, IL10RA and IFNGR were examined by the reverse transcription-polymerase chain reaction (RT-PCR), single-strand conformation polymorphism (SSCP), restriction fragment length polymorphism (RFLP) method and DNA sequencing.
Results The mRNA expression of Th2 cytokine receptors was positively detected in 100% of subjects, including active SLE group(group Ⅰ), inactive SLE group(group Ⅱ) and healthy control group(groupⅢ). The mean level of IL-4R mRNA expression in group Ⅰ , Ⅱ or Ⅲ was 0.604±0.147, 0.40±0.13 or 0.37±0.07, respectively. Compared with group Ⅱ or group Ⅲ, the mean level of IL-4R mRNA expressions was markedly increased in group Ⅰ (P<0.05), with non-statistical difference between group Ⅱ and groupⅢ (P=0.315). The mean level of IL-6R mRNA expressions in group I , II or III was 0.902±0.273, 0.519±0.11 or 0.573±0.24, respectively. Compared with group Ⅱ or group Ⅲ, the mean level of IL-6R mRNA expression in group Ⅰ was markedly increased (P<0.05), with non-statistical difference between group Ⅱ and group Ⅲ (P=0.289). The mean levels of IL-IOR mRNA expression in
引文
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15. Joshi B.H, Leland Pamela, Asher Anthony, et al. In situ Expression of Interleukin-4 (IL-4) Receptors in Human Brain Tumors and Cytotoxicity of a Recombinant IL-4 Cytotoxin in Primary Glioblastoma Cell Cultures. Cancer Research 61,8058-8061,Novmber 15,2001
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22. Jurlander Jesper, Lai Chun-fai, Tan Jimmy, et al. Characterization of Interleukin-10 Receptor Expression on B-cell Chronic Lymphocytic Leukemia Cells. Blood Vol.89 No.11(June 1), 1997: pp4146-4152
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24. Taniyama Tadayoshi, Takai Setsuo, Miyazaki Emi, et al.The human interleukin-10 receptor gene maps to chromosome 1 lq23.3.Hum Genet(1995)95;99-101
25. Nishimoto Norihiro, Kishimoto Tadamitsu, Yoshizaki Kazuyuki. Anti-interleukin 6 receptor antibody treatment in rheumatic disease. Ann Rheum Dis 2000;59(suppl I):i21-i27
26. Taha Rame A., Leung Donald Y.M, Ghaffar Omar, et al.In vivo expression of cytokine receptor mRNA in atopic dermatitis. J Allergy Clin Immunol 1998;102:245-50
27. Rivas Dolores, Mozo Lourdes, Zamorano Jose, et al. Upregulated Expression of IL-4 Receptors and Increased Levels of IL-4 in Rheumatoid Arthritis patients. Journal ofAutoimmunity(1995)8, 587-600.
28. Nakashima H, Akahoshi M, Tanaka Y, et al. Polymorphisms within the interleukin-10 receptor cDNA gene (IL10R) in Japanese patients with systemic lupus erythematosus. Rheumatology 1999; 38: 1142-44
29. Joshi B. H, Leland Pamela, Asher Anthony, et al. In Situ Expression of Interleukin-4 (IL-4) Receptors in Human Brain Tumors and Cytotoxicity of a Recombinant IL-4 Cytotoxin in Primary Glioblastoma Cell Culture. Cancer Research 61, 8058-61, November 15, 2001
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11. Kruse S, Japha T, Tedner M, et al. The polymorphisms S503P and Q575R in the interleukin-4 receptor a gene are associated with atopy and influence the signal transduction. Immunology 1999; 96:365-371
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13. Parry R.G, Gillespie K.M, Parnham A., et al. Interleukin-4 and interleukin-4 receptor polymorphisms in minimal change nephropathy. Clinical science 1999; 96:665-668
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18. Tanaka Yosuke, Nakashima Hitoshi, Otsuka Takeshi, et al. Detection of polymorphisms within the human IL10 receptor cDNA gene sequence by RT-PCR RFLP. Immunogenetics 1997; 46: 439-41
19. Nakashima H, Akahoshi M, tanaka Y, et al. Polymorphisms within the interleukin-10 receptor cDNA gene(IL10R) in Japanese patients with systemic lupus erythematosus. Rheumatology 1999; 38: 1142-4
2. Chan RW, Tam LS, Li EK, et al. Inflammatory cytokine gene expression in the urinary sediment of patients with lupus nephritis. Arthritis Rheum. 2003 May;48(5): 1326-31.
3. Uhm WS, Na K, Song GW, et al. Cytokine balance in kidney ti ssue from lupus nephritis patients. Rheumatology (Oxford). 2003 Aug; 42(8):935-8. Epub 2003 Mar 31.
4. Chen S, Hu D, Shi X, et al. The relationship between Th1/Th2-type cells and disease activity in patients with systemic lupus erythematosus. Chin Med J (Engl). 2000 Oct;113 (10): 877-80.
5. Min DJ, Cho ML, Cho CS,et al. Decreased production of interleukin-12 and interferon-gamma is associated with renal involvement in systemic lupus erythematosus. Scand J Rheumatol. 2001;30(3): 159-63.
6. Parry, R.G, Kathleen M. Gillespie Peter W. Mathieson. Effects of Type 2 Cttokines on Glomerular Epithelial Cells. Exp Nephrol 2001;9:275-283
7. Akira furusu, Masanobu miyazaki, Takehiko koji et al. Involvement of IL-4 in Human Glomerulonephritis: An in situ Hybridization Study of IL-4mRNA and IL-4 Receptor mRNA. J Am Soc Nephrol 8: 730-741,1997
8. Koji Kawakami, Pamela leland, Puri R.K. Structure, Function and Targeting of Interleukin 4 Receptors on Human Head and Neck Cancer Cells. Cancer Resaetrch 60,2981-2987, June 1, 2000
9. Joshi B.H, Pamela Leland, Anthony Asher et al. In situ Expression of Interleukin-4 (IL-4)
Receptors in Human Brain Tumors and Cytotoxicity of a Recombinant IL-4 Cytotoxin in Primary Glioblastoma Cell Cultures. Cancer Research 61,8058-8061,Novmber 15,2001
10. Kotsimbos T. C, Ghaffar Omar, Minshall E.M. et al. Expression of the IL-4 receptor a-subunit is increased in bronchial biopsy specimens from atopic and nonatopic asthmatic subjects. J Allergy Clin Immunol 1998;102:859-66
11. Andre Gessner, Martin Rollinghoff. Biologic Functions and Signaling of the interleukin-4 Receptor Complexes. Immunobioogy(1999/2000) 201,285-307
12. Rivas Dolores, Mozo Lourdes, Zamorano Jose, et al. Upregulated Expression of IL-4 Receptors and Increased Levels of IL-4 in Rheumatoid Arthritis patients.Journal of Autoimmunity(1995)8, 587-600.
13. Joshi B.H, Leland Pamela, Asher Anthony, et al. In Situ Expression of Interleukin-4 (IL-4) Receptors in Human Brain Tumors and Cytotoxicity of a Recombinant IL-4 Cytotoxin in Primary Glioblastoma Cell Culture. Cancer Research 61,8058-61,November 15,2001
14. Obiri N.I, Siegel J.P, Varricchio F, et al. Expression of high-affinity IL-4 receptors on human melanoma,ovarian and breast carcinoma cells.Clin Exp Immunol 1994;95:148-55
15. Lahm Harald, Schnyder Bruno, Wyniger Josiane, et al. Growth inhibition of human colorectal-carcinoma cells by interleukin-4 and expression of function interleukin-4 receptors. Int. J. Cancer: 59,440-447(1997)
16. Dubois G.R, Schweizer R.C, Versluis Coraline, et al. Human Eosinophils Constitutively express a Functional Interleukin-4 Receptor: Interleukin-4-Induced Priming of Chemotactic Responses and Induction of PI-3 Kinase Activity.Am.J.Respir.Cell Mol.Biol.l9:691-9
17. Jonees Simon A, Horiuchi Sankichi, Topley Nicholas, et al. The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J.15,43-58(2001)
18. Udagawa Nobuyuki, Takahashi Naoyuki, Katagiri Takenobu et al. Interleukin(IL)-6 Induction of Osteoclast Differentiation Depends on IL-6 Receptors Expressed on Osteoblatic cells But
not on Osteoclast Progenitors. J. Exp.Med. Volume 182 November 1995, 1461-1468
19. Marz P, Gadient R.A., Otten U. Expression of interleukkin-6 receptor (IL-6R) and gpl30 mRNA in PC12 cells and sympathetic neurons: modulation by tumor necrosis factor α(TNF-α). Brain Research 706 (1996) 71-79
20. Szczepek A. J, Belch A. R., Pilarski L.M. Expression of IL-6 and IL-6 receptors by circulating clonotypic B cells in multiple myeloma: Potential for autocrine and paracrine networks. Experimental Haematology 29(2001)1076-1081
21. Diamant Marcus, Hansent M.B, Rieneck Klaus et al. Diffrential Interleukin-6(Il-6) Responses Of Three Established Myeloma Cell Lines In The Presence Of Soluble Human Il-6 Receptors. Leukemia Research Vol.20, No.4, 291-301,1996
22. Nishimoto Norihiro, Kishimoto Tadamitsu, Yoshizaki Kazuyuki. Anti-interleukin 6 receptor antibody treatment in rheumatic disease. Ann Rheum Dis 2000;59(suppl I):i21-i27
23. Kevin W. M, Rene de Waal Malefyt, Robert 1 et al. Interleukin-10 and the Interleukin-10 Receptor. Annu. Rev. Immunol. 2001, 19:683-765
24. Avdiushko Rit, Hongo David, Helene Lake-Bullock et al. IL-10 receptor dysfunction in macrophages during chronic inflammation. J Leukoc. Biol. 70:624-632; 2001
25. Jurlander Jesper, Lai Chun-fai, Tan Jimmy et al. Characterization of Interleukin-10 Receptor Expression on B-cell Chronic Lymphocytic Leukemia Cells. Blood Vol.89 No. 11 (June 1), 1997: pp4146-4152
26. Iannone F, De Bari C, Dell Accio F et al. Interleukin-10 and interleukin-10 receptor in human osteoarthritic and healthy chondrocytes. Clin Exp Rheumatol 2001 Mar-Apr; 19(2): 139-45
27. Taniyama Tadayoshi, Takai Setsuo, Miyazaki Emi et al.The human interleukin-10 receptor gene maps to chromosome 1 lq23.3.Hum Genet(1995)95;99-101
28. Rame A.Taha, Donald Y.M.Leung, Omar Ghaffar et al. In vivo expression of cytokine receptor mRNA in atopic dermatitis.J Allergy Clin Immunol 1998;102:245-50
29. Nakashima H, Akahoshi M, Tanaka Y, et al. Polymorphisms within the interleukin-10 receptor cDNA gene (IL10R) in Japanese patitents with systemic lupus erythematosus. Rheumatology 1999; 38: 1142-44
30. Hatanaka H, Abe Y, Kamiya T, et al. Clinical implications of interleukin (IL) -10 induced by non-small-cell lung cancer. Annals of Oncology 11: 815-9,2000
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