IL-10基因启动子区单核苷酸多态性与乙型肝炎病毒感染的相关研究
|
摘要
目的：功能性DNA多态性影响基因表达以及血浆或组织中IL-10的水平。我们的病例对照研究主要是要探索白细胞介素-10(IL-10)基因启动子区域-1082,-592位点单核苷酸多态性(SNP)与乙型肝炎病毒感染后临床转归之间的关系.
方法：我们采用病例-对照研究的方法,分别收集175例乙肝患者和153例正常对照者的外周静脉血,以基因组DNA为模板,采用聚合酶链反应-限制性片段长度多态性方法(PCR-RFLP)分析IL-10-592A/C位点和IL-10-1082A/G位点基因分布及等位基因频率,并结合临床资料初步评价IL-10-592A/C位点和IL-10-1082A/G点基因多态性与乙型肝炎病毒感染后的相关性研究。用x2检验进行统计学分析。
结果：①中国山西地区汉族人群中IL-10-592A/C基因多态性存在AA、AC和CC三种基因型,但这三种基因型的分布在患者组和对照组无统计学差异,且在患者组各种临床分型的基因型分布比较中亦无统计学差异。②IL-10-1082位点在正常对照组有AA,AG,GG三种基因型,而患者组只发现AA,AG两种基因型。经统计学分析,在基因型分布上,患者组和对照组无统计学差异。患者组各临床分型组进行比较,慢性乙型肝炎组与急性乙型肝炎组,重症肝炎组比较均有统计学差异(P值<0.001,<0.05)；而与肝硬化组却无明显统计学差异。另外,肝硬化组与急性乙型肝炎组基因型分布亦有统计学差异(P=0.020)。
结论：IL-10-592A/C位点和IL-10-1082A/G位点的SNP与乙型病毒性肝炎易感性之间并无关联性。而IL-10-1082A等位基因及AA基因型与乙肝病毒感染及感染后转归相关。
Objective To investigate the correlation between the single nuclertide polymorphism in the promoter region of interleukin-10(IL-10) gene and the clinical phenotypes of hepatitis B virus(HBV)infection in Chinese population。
Methods A retrospective case-control study design was applied for the present study. Using genomic DNA as templates, The genotypes of-1082 and-592 loci in the promoter region of IL-10 were analysis by polymerase chain-restriction fragment length polymorphism method (PCR-RFLP) in 175 cases of patients with hepatitis B and 153 cases of the control.And Preliminary evaluate the association between the genotypes of-1082 and-592 loci in the promoter region of interleukin-10 polymorphisms with hepatitis B virus infection consequence.Chi-square test (χ2 test) was used for statistical.
Results Genotype AA,AC,CC in loci-592 in the promoter region of IL-10 were found in both patients group and the control group from Chinese Han population of Shanxi, and the genotypes distribution in two groups has no significant difference (P>0.05). The-1082AA and-1082AG genotype in IL-10 promoter region were only found in the group of patients with hepatitis B, but-1082 A A,-1082AG and-1082GG genotypes were all found in the control group. the genotypes distribution in two groups has no significant difference.But the distribution frequences of-1082A allele and-1082AA genotype in IL-10 promoter region were significantly higher in the group of patients with chronic hepatitis B than the group of patients with acute hepatitis B and the group of patients with sever hepatitis B (P 0.001,0.05)。Morever,the distribution between the group of Cirrhosis and the group of acute hepatitis B has significant difference(p=0.020).
Conclusion 1.IL-10-592A/C and IL-10-1082A/G Single nucleotide polymorphism with the occurrence of hepatitis B has no significant difference.2.The-1082A allele and -1082AA genotype in IL-10 promoter region may be associated with the chronic hepatitis B infection.
方法：我们采用病例-对照研究的方法,分别收集175例乙肝患者和153例正常对照者的外周静脉血,以基因组DNA为模板,采用聚合酶链反应-限制性片段长度多态性方法(PCR-RFLP)分析IL-10-592A/C位点和IL-10-1082A/G位点基因分布及等位基因频率,并结合临床资料初步评价IL-10-592A/C位点和IL-10-1082A/G点基因多态性与乙型肝炎病毒感染后的相关性研究。用x2检验进行统计学分析。
结果：①中国山西地区汉族人群中IL-10-592A/C基因多态性存在AA、AC和CC三种基因型,但这三种基因型的分布在患者组和对照组无统计学差异,且在患者组各种临床分型的基因型分布比较中亦无统计学差异。②IL-10-1082位点在正常对照组有AA,AG,GG三种基因型,而患者组只发现AA,AG两种基因型。经统计学分析,在基因型分布上,患者组和对照组无统计学差异。患者组各临床分型组进行比较,慢性乙型肝炎组与急性乙型肝炎组,重症肝炎组比较均有统计学差异(P值<0.001,<0.05)；而与肝硬化组却无明显统计学差异。另外,肝硬化组与急性乙型肝炎组基因型分布亦有统计学差异(P=0.020)。
结论：IL-10-592A/C位点和IL-10-1082A/G位点的SNP与乙型病毒性肝炎易感性之间并无关联性。而IL-10-1082A等位基因及AA基因型与乙肝病毒感染及感染后转归相关。
Objective To investigate the correlation between the single nuclertide polymorphism in the promoter region of interleukin-10(IL-10) gene and the clinical phenotypes of hepatitis B virus(HBV)infection in Chinese population。
Methods A retrospective case-control study design was applied for the present study. Using genomic DNA as templates, The genotypes of-1082 and-592 loci in the promoter region of IL-10 were analysis by polymerase chain-restriction fragment length polymorphism method (PCR-RFLP) in 175 cases of patients with hepatitis B and 153 cases of the control.And Preliminary evaluate the association between the genotypes of-1082 and-592 loci in the promoter region of interleukin-10 polymorphisms with hepatitis B virus infection consequence.Chi-square test (χ2 test) was used for statistical.
Results Genotype AA,AC,CC in loci-592 in the promoter region of IL-10 were found in both patients group and the control group from Chinese Han population of Shanxi, and the genotypes distribution in two groups has no significant difference (P>0.05). The-1082AA and-1082AG genotype in IL-10 promoter region were only found in the group of patients with hepatitis B, but-1082 A A,-1082AG and-1082GG genotypes were all found in the control group. the genotypes distribution in two groups has no significant difference.But the distribution frequences of-1082A allele and-1082AA genotype in IL-10 promoter region were significantly higher in the group of patients with chronic hepatitis B than the group of patients with acute hepatitis B and the group of patients with sever hepatitis B (P 0.001,0.05)。Morever,the distribution between the group of Cirrhosis and the group of acute hepatitis B has significant difference(p=0.020).
Conclusion 1.IL-10-592A/C and IL-10-1082A/G Single nucleotide polymorphism with the occurrence of hepatitis B has no significant difference.2.The-1082A allele and -1082AA genotype in IL-10 promoter region may be associated with the chronic hepatitis B infection.
引文
性乙型肝炎组,慢性乙型肝炎组,肝硬化组,重症肝炎组IL-10-1082位点各基因型的分布,发现慢性肝炎组与肝硬化组分别与急性肝炎组比较分布均有统计学差异(P值分别为<0.001,0.020),提示IL-10-1082多态性可能与HBV感染后转归有相关性。
1. Rapicetta M, Ferrari C, Levrero M. Viral determinants and host immune responses in the pathogenesis of HBV infection. Journal of Medical Virology,2002,67(3):454-457.
2. Lee WM. Hepatitis B virus infections. N Engl J Med,1997,337 (24):1733-1745.
3. Malik AH, Lee WM. Hepatitis B therapy:the polt thickens.Hepatology,2000,30(3):579-581.
4. Morovic M.Treatment of chronic hepatitis B.Acta Med Croatica,2005,59 (5):429-432.Kobierski J,Emerich J,Krolikowska,et al. Lymph node metastasis as a prognostic factor in cervical carcinoma[J].Ginekol Pol.2002;73(11):925-929. Prostate.2008;68(13):1443-1449.
5. Hyodo N, Tajimi M, Ugajin T, et al. Frequencies of interferon-gamma and interleukin-10 secreting cells in peripheral blood mononuclear cells and liver infiltrating lymphocytes in chronic hepatitis B virus infection. Hepatol Res,2003,27:109-116.
6. Hyodo N, Nakamura I, Imawari M. Hepatitis B core antigen stimulates interleukin-10 secretion by both T cells and monocytes from peripheral blood of patients with chronic hepatitis B virus infection. Clin Exp Immunol,2004,135:462-466.
7.曾朝阳,李桂源.单核苷酸多态性.国外医学分子生物学分册,2001,23：149-151.
8. Lopez-Maderuelo D, Arnalich F, Serantes R, et al. Interferon-γand interleukin-10 gene polymorphisms in pulmonary tuberculosis. Am J Respir Crit Care Med,2003,167:970-975.
9. Raitala A.Pertovaara M, Karjalainen J, et al. Association of interferon-gamma+874(T/A)single nucleotide polymorphism with the rate of tryptophan catabolism in healthy individuals. Scand J Immunol,2005,61:387-390.
10. Platzer C,Volk HD and Platzer M.5'noncoding sequence of human IL-10gene obtained by oligo-cassette PCR walking. DNA Seq,1994,4(6):399-401.
11. Westendorp RG, Langermans JA, Huizinga TW, et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet,1997,349(9046):170-173.
12. Shin HD, Park BL, Kim LH, et al. Interleukin 10 haplotype associated with increased risk of hepatocellular carcinoma. Hum Mol Genet,2003,12(8):901-906.
13. Ben-Ari Z, Mor E, Papo O, et al. Cytokine gene polymorphisms in patients infected with hepatitis B virus. Am J Gastroenterol,2003,98 (1):144-150.
14. Zhu QR, Gu SQ, Yu H, et al. Relationship between cytokine gene polymorphism and susceptibility to hepatitis B virus intrauterine infection.Zhonghua Liu Xing Bing Xue Za Zhi,2005,26(4):236-239.
15. Zhang PA, Li Y and Yang XS. Associated study on interleukin 10 gene promoter polymorphisms related to hepatitis B virus infection in Chinese Han population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi,2006,23(4):410-414.
16.刘道洁、刘英、李卓,等.慢性重型乙型肝炎患者白细胞介素-10基因多态性相关性研究.中华微生物学和免疫学杂志,2007,27(2)：129-132.
17.严艳,李卓,李洪权,等.细胞细胞介素-10基因多态性与乙型肝炎病毒感染的关系.世界华人消化杂志，2006,14(36)：3529-3533.
18.张健,李卫宁,林华.IL-10基因启动子区-592A/C位点多态性与HBV感染转归的关系.现代检验医学杂志,2007,22(3)：81-84.
19. Spits H and de Waal Malefyt R. Functional characterization of human IL-10. Int Arch Allergy Immunol,1992,99(1):8-15.
20. Tozaki T,Choi-Miura NH,Taniyama M, et al. SNP analysis of the inter-alpha-trypsin inhibitor family heavy chain-related protein (IHRP) gene by a fluorescence-adapted SSCP method BMC Med Genet,2002,3:6.
21.陈蕊雯,段世伟,蔡青,等.肿瘤坏死因子a的单核苷酸多态性与中国汉族人强直性脊柱炎的关联分析.第二军医大学学报,2004,25(2)：120-124. 带IL-10-ht2单体型者,肝细胞癌的发病年龄降低。该研究表明,IL-10-ht2单体型,通过上调IL-10水平,加速慢性乙型肝炎病毒感染的发展进程,尤其是肝细胞癌的发生。Ben-Ari等通过研究得出不同的结论,认为IL-10启动子区SNPs对IL-10表达水平无影响。Zhu等 将HBV宫内感染的高.危儿童分为免疫失败组和免疫有效组,以正常儿童做对照,研究结果发现IL-10启动子区1082位点G等位基因与预防HBV宫内感染相关。Zhang等对中国汉族人群进行IL-10多态性与乙型肝炎病毒(hepatitis b virus, HBV)易感性及临床表型关系的研究,结果证明IL-10启动子区SNPs与HBV易感性及感染后HBV DNA复制不相关,但启动子819T/C和592A/C与乙肝患者肝脏炎症反应呈现相关性。刘道洁等研究认为IL-10启动子区1082基因AA型,592基因AC、 CC型及819基因TC型与慢性重型肝炎的发生有关,说明1082 AA,592 AC、 CC及819TC基因携带者患慢性重型肝炎的风险相对较大,从而得出了IL-10启动子区基因多态性与HBV感染所致肝病肝损害进展和重型肝炎发生可能有关的结论。严艳等研究证明IL-10-1082A等位基因及AA基因型-819T等位基因及TT基因型在慢性乙型肝炎患者组的频率高于自限性感染者组和乙肝病毒携带者组,-592C/A等位基因频率在三组的分布无统计学差异。因此,IL-10基因启动子多态性与乙型肝炎病毒感染后临床发展过程可能相关。张健等研究结果也支持汉族人IL-10-592A/C位点等位基因多态性可能与人群对HBV易感性及感染后病毒血症水平无显著相关性,但该位点基因多态性与HBV感染后的肝脏炎症反应有关。
迄今,国内外学者对IL-10及其基因多态性进行了广泛的研究,IL-10作为机体重要的免疫调节性细胞因子,在不同疾病过程中的表达水平及作用,以及其单核苷酸多态性对病毒性肝炎易感性、疾病严重程度及治疗敏感性等多方面研究,不同文献报道不尽相同,我们旨在增加样本含量,综合考虑多因素,将实验和临床研究不断深入,争取为将IL-10有效应用于临床奠定基础,进而为尽早预防肝病的进展及原发性肝细胞癌的发生做出些许贡献
[1].Moore KW, O'Garra A, de-Waal Malefyt R, et al.Interleukin-10.Ann RevImmunol,1993,11:165-190.
[2].Donnelly RP, Dickensheets H, Finbloom DS.The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes.J Interferon Cytokine Res.1999 Jun;19(6):563-73.
[3]Krebs DL, Hilton DJ.SOCS:physiological suppressors of cytokine bn signaling.JCell Sci.2000 Aug;113(Pt16):2813-9.
[4].O'Farrell AM, Liu Y, Moore KW, et al.IL-10 inhibits macrophage activation and proliferation by distinct signaling mechanisms:evidence for Stat3-dependent and-independent pathways.EMBO J.1998 Feb 16; 17(4):1006-18
[5].Willems F,Marchant A,Delville JP,et al.Interleukin-10 inhibits B7 and intercellular adhesion molecule-1 expression on human monocytes.Eur J Immunol,1994,24(4):1007-1009.
[6].Fiorentino DF,Zlotnik A,Mosmann TR,et al.IL-10 inhibits cytokine production by activated macrophages.J.Immunol,1991,147(11):3815-3822.
[7].Fiorentino DF,Zlotnik A,Vieira P,et al.IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells.J.Immunol,1991,146(10):3444-3451.
[8].Taga K,Mostowski H and Tosato G.Human interleukin-10 can directly inhibit T-cell growth.Blood,1993,81(11):2964-2971.
[9].de Waal Malefyt R,Yssel H and de Vries JE.Direct effects of IL-10 on subsets of human CD4+T cell clones and resting T cells.Specific inhibition of IL-2 production and proliferation.J Immunol,1993,150(11):4754-4765.
[10].Del Prete G,De Carli M,Almerigogna F,et al.Human IL-10 is produced by both type 1 helper(Thl)and type 2 helper(Th2)T cell clones and inhibits their antigen-specific proliferation and cytokine production.J Immunol,1993,150(2):353-360.
[11].Liu Y,Wei SH,Ho AS,et al.Expression cloning and characterization of a human IL-10 receptor.J Immunol 1994,152(4):1821-1829.
[12].Groux H,Bigler M,de Vries JE,et al.Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+T cells.J Exp Med,1996,184(1):19-29.
[13].Groux H,Bigler M,de Vries JE,et al.Inhibitory and Stimulatory Effects of IL-10 on Human CD8+T Cells.J Immunol,1998,160(7):3188-3193.
[14].Santin AD,Hermonat PL,Ravaggi A,et al.Interleukin-10 Increases Thl Cytokine Production and Cytotoxic Potential in Human Papillomavirus-Specific CD8+Cytotoxic T Lymphocytes.J Virol,2000,74(10):4729-4737.
[15].Go NF,Castle BE,Barrett R,et al.Interleukin 10,a novel B cell stimulatory factor:unresponsiveness of X chromosome-linked immunodeficiency B cells. J Exp Med,1990,172(6):1625-1631.
[16].Levy Y and Brouet JC.Interleukin-10 prevents spontaneous death of germinal center B cells by induction of the bcl-2 protein.J Clin Invest,1994,93(1):424-428.
[17].Uejima Y,Takahashi K,Komoriya K,et al.Effect of interleukin-10 on anti-CD40-and interleukin-4-induced immunoglobulin E production by human lymphocytes.Int Arch Allergy Immunol,1996,110(3):225-232.
[18].Cai G,Kastelein RA and Hunter CA.IL-10 enhances NK cell proliferation, cytotoxicity and production of IFN-gamma when combined with IL-18.Eur J Immunol.1999,29(9):2658-26 65.
[19].Carson WE,Lindemann MJ,Baiocchi R,et al.The functional characterization of interleukin-10 receptor expression on human natural killercells.Blood.1995,85(12 ):3577-3585.
[20].Royer B,Varadaradjalou S,Saas P,et al.Autocrine regulation of cord blood-derived human mast cell activation by IL-10.J Allergy Clin Immunol,2001,108(1):80-86.
[21].Norton SK,Barnstein B,Brenzovich J,et al.IL-10 Suppresses Mast Cell IgE Receptor Expression and Signaling In Vitro and In Vivo.J Immunol,2008,180(5):2848-2854.
[22].Royer B,Varadaradjalou S,Saas P,et al.Inhibition of IgE-induced activation of human mast cells by IL-10.Clin Exp Allergy,2001,31 (5):694-704.
[23].Bundoc VG and Keane-Myers A.IL-10 confers protection from mast cell degranulation in a mouse model of allergic conjunctivitis.Exp Eye Res, 2007,85(4):575-579.
[24].Yoshidome H, Kato A, Edwards MJ, et al.Interleukin-10 suppresses hepatic ischemia/reperfusion injury in mice:implications of a central role for nuclear factor kappaB.Hepatology.1999 Jul;30(1):203-8.
[25].Louis H, Le Moine O, Peng MO, et al.Production and role of interleukin-10 in concanavalin a induced hepatitis in mice.Hepatology,1997,25:1382-1389.
[26].Yasuyuki E, Shigeo T, Hiroki T, et al.Liver specific injury induced by immunization with fusions of dendritic cell and hepatocyte or hepatoma cell.2000 年欧洲肝病年会会议论文集
[27].李玲,顾长海,王宇明等乙型肝炎患者血清和PBMC培养上清IL-2与IL-10的检测及意义第三军医大学报2001年第23卷第11期
[28].薛建亚,秦一中,韩絮琳等慢性乙型肝炎患者外周血单个核细胞分泌细胞因子的检测及其意义第二军医大学学报2000Jun；21(6)
[29].万谟彬,谭晓风,马大烈慢性乙型肝炎患者肝组织内白细胞介素10表达中国抗感染化疗杂志2003年2月28日第3卷第1期
[30].Meisel C,Vogt K,Platzer C,et al.Differential regulation of monocytic tumor necrosis factor-alpha and
interleukin-10 expression.Eur J Immunol,1996,26(7):1580-1586.
[31].Platzer C,Meisel C,Vogt K,et al.Up-regulation of monocytic IL-10 by tumor necrosis factor-alpha and cAMP elevating drugs.Int Immunol,1995,7(4):517-523.
[32].Platzer C,Fritsch E,Elstner T,et al.Cyclic adenosine monophosphate-responsive elements are involved in the transcriptional activation of thehuman IL-10 gene in monocytic cells.Eur J Immunol,1999,29(10):3098-3104.
[33].Platzer C,Docke WD,Volk HD,et al.Catecholamines trigger IL-10 release in acute systemic stress reaction by direct stimulation of its promoter/enhancer activity in monocytic cells.J Neuroimmunol,2000,105(1):31-38.
[34].Platzer C,Volk HD and Platzer M.5'noncoding sequence of human IL-10 gene obtained by oligo-cassette PCR walking.DNA Seq,1994,4(6):399-401.
[35].Westendorp RG,Langermans JA,Huizinga TW,et al.Genetic influence on cytokine production and fatal meningococcal disease.Lancet,1997,349(9046):170-173.
[36].Westendorp RG,Langermans JA,Huizinga TW,et al.Genetic influence on cytokine production and fatal meningococcal disease.Lancet,1997,349(904170-173.
[37].Gallagher PM,Lowe G,Fitzgerald T,et al.Association of IL-1 polymorphism with severity of illness in community acquired pneumoni Thorax,2003,58(2):154-156.
[38].Lio D,Licastro F,Scola L,et al.Interleukin-10 promoter polymorphism in sporadic Alzheimer's disease.Genes Immun,2003,4(3):234-238.
[39].Shin HD,Park BL,Kim LH,et al.Interleukin 10 haplotype associated wit increased risk of hepatocellular carcinoma.Hum Mol Genet,2003,12(8901-906.
[40].Ben-Ari Z,Mor E,Papo O,et al.Cytokine gene polymorphisms in patien infected with hepatitis B virus.Am J Gastroenterol,2003,98(1):144-150.
[41].Zhu QR,Gu SQ,Yu H,et al.Relationship between cytokine gen polymorphism and susceptibility to hepatitis B virus intrauterine infectio Zhonghua Liu Xing Bing Xue Za Zhi,2005,26(4):236-239.
[42].Zhang PA,Li Y and Yang XS.Associated study on interleukin 10 gen promoter polymorphisms related to hepatitis B virus infection in Chinese Ha population.Zhonghua Yi Xue Yi Chuan Xue Za Zhi,2006,23(4):410-414.
[43].刘道洁、刘英、李卓,等.慢性重型乙型肝炎患者白细胞介素-10基因多态性相关性研究.中华微生物学和免疫学杂志,2007,27(2)：129-132.
[44].严艳,李卓,李洪权,等.细胞细胞介素-10基因多态性与乙型肝炎病毒感染的关系.世界华人消化杂志,2006,14(36)：3529-3533.
[45].张健,李卫宁,林华.IL-10基因启动子区-592A/C位点多态性与HBV感染转归的关系.现代检验医学杂志,2007,22(3)：81-84.
[46]李艳杰,龙火生,李影,杨公社。单核苷酸多态性的研究进展和应用[J].Journal of Animal Science and Veterinary Medicine;2003;22(4):16-18.
1. Rapicetta M, Ferrari C, Levrero M. Viral determinants and host immune responses in the pathogenesis of HBV infection. Journal of Medical Virology,2002,67(3):454-457.
2. Lee WM. Hepatitis B virus infections. N Engl J Med,1997,337 (24):1733-1745.
3. Malik AH, Lee WM. Hepatitis B therapy:the polt thickens.Hepatology,2000,30(3):579-581.
4. Morovic M.Treatment of chronic hepatitis B.Acta Med Croatica,2005,59 (5):429-432.Kobierski J,Emerich J,Krolikowska,et al. Lymph node metastasis as a prognostic factor in cervical carcinoma[J].Ginekol Pol.2002;73(11):925-929. Prostate.2008;68(13):1443-1449.
5. Hyodo N, Tajimi M, Ugajin T, et al. Frequencies of interferon-gamma and interleukin-10 secreting cells in peripheral blood mononuclear cells and liver infiltrating lymphocytes in chronic hepatitis B virus infection. Hepatol Res,2003,27:109-116.
6. Hyodo N, Nakamura I, Imawari M. Hepatitis B core antigen stimulates interleukin-10 secretion by both T cells and monocytes from peripheral blood of patients with chronic hepatitis B virus infection. Clin Exp Immunol,2004,135:462-466.
7.曾朝阳,李桂源.单核苷酸多态性.国外医学分子生物学分册,2001,23：149-151.
8. Lopez-Maderuelo D, Arnalich F, Serantes R, et al. Interferon-γand interleukin-10 gene polymorphisms in pulmonary tuberculosis. Am J Respir Crit Care Med,2003,167:970-975.
9. Raitala A.Pertovaara M, Karjalainen J, et al. Association of interferon-gamma+874(T/A)single nucleotide polymorphism with the rate of tryptophan catabolism in healthy individuals. Scand J Immunol,2005,61:387-390.
10. Platzer C,Volk HD and Platzer M.5'noncoding sequence of human IL-10gene obtained by oligo-cassette PCR walking. DNA Seq,1994,4(6):399-401.
11. Westendorp RG, Langermans JA, Huizinga TW, et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet,1997,349(9046):170-173.
12. Shin HD, Park BL, Kim LH, et al. Interleukin 10 haplotype associated with increased risk of hepatocellular carcinoma. Hum Mol Genet,2003,12(8):901-906.
13. Ben-Ari Z, Mor E, Papo O, et al. Cytokine gene polymorphisms in patients infected with hepatitis B virus. Am J Gastroenterol,2003,98 (1):144-150.
14. Zhu QR, Gu SQ, Yu H, et al. Relationship between cytokine gene polymorphism and susceptibility to hepatitis B virus intrauterine infection.Zhonghua Liu Xing Bing Xue Za Zhi,2005,26(4):236-239.
15. Zhang PA, Li Y and Yang XS. Associated study on interleukin 10 gene promoter polymorphisms related to hepatitis B virus infection in Chinese Han population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi,2006,23(4):410-414.
16.刘道洁、刘英、李卓,等.慢性重型乙型肝炎患者白细胞介素-10基因多态性相关性研究.中华微生物学和免疫学杂志,2007,27(2)：129-132.
17.严艳,李卓,李洪权,等.细胞细胞介素-10基因多态性与乙型肝炎病毒感染的关系.世界华人消化杂志，2006,14(36)：3529-3533.
18.张健,李卫宁,林华.IL-10基因启动子区-592A/C位点多态性与HBV感染转归的关系.现代检验医学杂志,2007,22(3)：81-84.
19. Spits H and de Waal Malefyt R. Functional characterization of human IL-10. Int Arch Allergy Immunol,1992,99(1):8-15.
20. Tozaki T,Choi-Miura NH,Taniyama M, et al. SNP analysis of the inter-alpha-trypsin inhibitor family heavy chain-related protein (IHRP) gene by a fluorescence-adapted SSCP method BMC Med Genet,2002,3:6.
21.陈蕊雯,段世伟,蔡青,等.肿瘤坏死因子a的单核苷酸多态性与中国汉族人强直性脊柱炎的关联分析.第二军医大学学报,2004,25(2)：120-124. 带IL-10-ht2单体型者,肝细胞癌的发病年龄降低。该研究表明,IL-10-ht2单体型,通过上调IL-10水平,加速慢性乙型肝炎病毒感染的发展进程,尤其是肝细胞癌的发生。Ben-Ari等通过研究得出不同的结论,认为IL-10启动子区SNPs对IL-10表达水平无影响。Zhu等 将HBV宫内感染的高.危儿童分为免疫失败组和免疫有效组,以正常儿童做对照,研究结果发现IL-10启动子区1082位点G等位基因与预防HBV宫内感染相关。Zhang等对中国汉族人群进行IL-10多态性与乙型肝炎病毒(hepatitis b virus, HBV)易感性及临床表型关系的研究,结果证明IL-10启动子区SNPs与HBV易感性及感染后HBV DNA复制不相关,但启动子819T/C和592A/C与乙肝患者肝脏炎症反应呈现相关性。刘道洁等研究认为IL-10启动子区1082基因AA型,592基因AC、 CC型及819基因TC型与慢性重型肝炎的发生有关,说明1082 AA,592 AC、 CC及819TC基因携带者患慢性重型肝炎的风险相对较大,从而得出了IL-10启动子区基因多态性与HBV感染所致肝病肝损害进展和重型肝炎发生可能有关的结论。严艳等研究证明IL-10-1082A等位基因及AA基因型-819T等位基因及TT基因型在慢性乙型肝炎患者组的频率高于自限性感染者组和乙肝病毒携带者组,-592C/A等位基因频率在三组的分布无统计学差异。因此,IL-10基因启动子多态性与乙型肝炎病毒感染后临床发展过程可能相关。张健等研究结果也支持汉族人IL-10-592A/C位点等位基因多态性可能与人群对HBV易感性及感染后病毒血症水平无显著相关性,但该位点基因多态性与HBV感染后的肝脏炎症反应有关。
迄今,国内外学者对IL-10及其基因多态性进行了广泛的研究,IL-10作为机体重要的免疫调节性细胞因子,在不同疾病过程中的表达水平及作用,以及其单核苷酸多态性对病毒性肝炎易感性、疾病严重程度及治疗敏感性等多方面研究,不同文献报道不尽相同,我们旨在增加样本含量,综合考虑多因素,将实验和临床研究不断深入,争取为将IL-10有效应用于临床奠定基础,进而为尽早预防肝病的进展及原发性肝细胞癌的发生做出些许贡献
[1].Moore KW, O'Garra A, de-Waal Malefyt R, et al.Interleukin-10.Ann RevImmunol,1993,11:165-190.
[2].Donnelly RP, Dickensheets H, Finbloom DS.The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes.J Interferon Cytokine Res.1999 Jun;19(6):563-73.
[3]Krebs DL, Hilton DJ.SOCS:physiological suppressors of cytokine bn signaling.JCell Sci.2000 Aug;113(Pt16):2813-9.
[4].O'Farrell AM, Liu Y, Moore KW, et al.IL-10 inhibits macrophage activation and proliferation by distinct signaling mechanisms:evidence for Stat3-dependent and-independent pathways.EMBO J.1998 Feb 16; 17(4):1006-18
[5].Willems F,Marchant A,Delville JP,et al.Interleukin-10 inhibits B7 and intercellular adhesion molecule-1 expression on human monocytes.Eur J Immunol,1994,24(4):1007-1009.
[6].Fiorentino DF,Zlotnik A,Mosmann TR,et al.IL-10 inhibits cytokine production by activated macrophages.J.Immunol,1991,147(11):3815-3822.
[7].Fiorentino DF,Zlotnik A,Vieira P,et al.IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells.J.Immunol,1991,146(10):3444-3451.
[8].Taga K,Mostowski H and Tosato G.Human interleukin-10 can directly inhibit T-cell growth.Blood,1993,81(11):2964-2971.
[9].de Waal Malefyt R,Yssel H and de Vries JE.Direct effects of IL-10 on subsets of human CD4+T cell clones and resting T cells.Specific inhibition of IL-2 production and proliferation.J Immunol,1993,150(11):4754-4765.
[10].Del Prete G,De Carli M,Almerigogna F,et al.Human IL-10 is produced by both type 1 helper(Thl)and type 2 helper(Th2)T cell clones and inhibits their antigen-specific proliferation and cytokine production.J Immunol,1993,150(2):353-360.
[11].Liu Y,Wei SH,Ho AS,et al.Expression cloning and characterization of a human IL-10 receptor.J Immunol 1994,152(4):1821-1829.
[12].Groux H,Bigler M,de Vries JE,et al.Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+T cells.J Exp Med,1996,184(1):19-29.
[13].Groux H,Bigler M,de Vries JE,et al.Inhibitory and Stimulatory Effects of IL-10 on Human CD8+T Cells.J Immunol,1998,160(7):3188-3193.
[14].Santin AD,Hermonat PL,Ravaggi A,et al.Interleukin-10 Increases Thl Cytokine Production and Cytotoxic Potential in Human Papillomavirus-Specific CD8+Cytotoxic T Lymphocytes.J Virol,2000,74(10):4729-4737.
[15].Go NF,Castle BE,Barrett R,et al.Interleukin 10,a novel B cell stimulatory factor:unresponsiveness of X chromosome-linked immunodeficiency B cells. J Exp Med,1990,172(6):1625-1631.
[16].Levy Y and Brouet JC.Interleukin-10 prevents spontaneous death of germinal center B cells by induction of the bcl-2 protein.J Clin Invest,1994,93(1):424-428.
[17].Uejima Y,Takahashi K,Komoriya K,et al.Effect of interleukin-10 on anti-CD40-and interleukin-4-induced immunoglobulin E production by human lymphocytes.Int Arch Allergy Immunol,1996,110(3):225-232.
[18].Cai G,Kastelein RA and Hunter CA.IL-10 enhances NK cell proliferation, cytotoxicity and production of IFN-gamma when combined with IL-18.Eur J Immunol.1999,29(9):2658-26 65.
[19].Carson WE,Lindemann MJ,Baiocchi R,et al.The functional characterization of interleukin-10 receptor expression on human natural killercells.Blood.1995,85(12 ):3577-3585.
[20].Royer B,Varadaradjalou S,Saas P,et al.Autocrine regulation of cord blood-derived human mast cell activation by IL-10.J Allergy Clin Immunol,2001,108(1):80-86.
[21].Norton SK,Barnstein B,Brenzovich J,et al.IL-10 Suppresses Mast Cell IgE Receptor Expression and Signaling In Vitro and In Vivo.J Immunol,2008,180(5):2848-2854.
[22].Royer B,Varadaradjalou S,Saas P,et al.Inhibition of IgE-induced activation of human mast cells by IL-10.Clin Exp Allergy,2001,31 (5):694-704.
[23].Bundoc VG and Keane-Myers A.IL-10 confers protection from mast cell degranulation in a mouse model of allergic conjunctivitis.Exp Eye Res, 2007,85(4):575-579.
[24].Yoshidome H, Kato A, Edwards MJ, et al.Interleukin-10 suppresses hepatic ischemia/reperfusion injury in mice:implications of a central role for nuclear factor kappaB.Hepatology.1999 Jul;30(1):203-8.
[25].Louis H, Le Moine O, Peng MO, et al.Production and role of interleukin-10 in concanavalin a induced hepatitis in mice.Hepatology,1997,25:1382-1389.
[26].Yasuyuki E, Shigeo T, Hiroki T, et al.Liver specific injury induced by immunization with fusions of dendritic cell and hepatocyte or hepatoma cell.2000 年欧洲肝病年会会议论文集
[27].李玲,顾长海,王宇明等乙型肝炎患者血清和PBMC培养上清IL-2与IL-10的检测及意义第三军医大学报2001年第23卷第11期
[28].薛建亚,秦一中,韩絮琳等慢性乙型肝炎患者外周血单个核细胞分泌细胞因子的检测及其意义第二军医大学学报2000Jun；21(6)
[29].万谟彬,谭晓风,马大烈慢性乙型肝炎患者肝组织内白细胞介素10表达中国抗感染化疗杂志2003年2月28日第3卷第1期
[30].Meisel C,Vogt K,Platzer C,et al.Differential regulation of monocytic tumor necrosis factor-alpha and
interleukin-10 expression.Eur J Immunol,1996,26(7):1580-1586.
[31].Platzer C,Meisel C,Vogt K,et al.Up-regulation of monocytic IL-10 by tumor necrosis factor-alpha and cAMP elevating drugs.Int Immunol,1995,7(4):517-523.
[32].Platzer C,Fritsch E,Elstner T,et al.Cyclic adenosine monophosphate-responsive elements are involved in the transcriptional activation of thehuman IL-10 gene in monocytic cells.Eur J Immunol,1999,29(10):3098-3104.
[33].Platzer C,Docke WD,Volk HD,et al.Catecholamines trigger IL-10 release in acute systemic stress reaction by direct stimulation of its promoter/enhancer activity in monocytic cells.J Neuroimmunol,2000,105(1):31-38.
[34].Platzer C,Volk HD and Platzer M.5'noncoding sequence of human IL-10 gene obtained by oligo-cassette PCR walking.DNA Seq,1994,4(6):399-401.
[35].Westendorp RG,Langermans JA,Huizinga TW,et al.Genetic influence on cytokine production and fatal meningococcal disease.Lancet,1997,349(9046):170-173.
[36].Westendorp RG,Langermans JA,Huizinga TW,et al.Genetic influence on cytokine production and fatal meningococcal disease.Lancet,1997,349(904170-173.
[37].Gallagher PM,Lowe G,Fitzgerald T,et al.Association of IL-1 polymorphism with severity of illness in community acquired pneumoni Thorax,2003,58(2):154-156.
[38].Lio D,Licastro F,Scola L,et al.Interleukin-10 promoter polymorphism in sporadic Alzheimer's disease.Genes Immun,2003,4(3):234-238.
[39].Shin HD,Park BL,Kim LH,et al.Interleukin 10 haplotype associated wit increased risk of hepatocellular carcinoma.Hum Mol Genet,2003,12(8901-906.
[40].Ben-Ari Z,Mor E,Papo O,et al.Cytokine gene polymorphisms in patien infected with hepatitis B virus.Am J Gastroenterol,2003,98(1):144-150.
[41].Zhu QR,Gu SQ,Yu H,et al.Relationship between cytokine gen polymorphism and susceptibility to hepatitis B virus intrauterine infectio Zhonghua Liu Xing Bing Xue Za Zhi,2005,26(4):236-239.
[42].Zhang PA,Li Y and Yang XS.Associated study on interleukin 10 gen promoter polymorphisms related to hepatitis B virus infection in Chinese Ha population.Zhonghua Yi Xue Yi Chuan Xue Za Zhi,2006,23(4):410-414.
[43].刘道洁、刘英、李卓,等.慢性重型乙型肝炎患者白细胞介素-10基因多态性相关性研究.中华微生物学和免疫学杂志,2007,27(2)：129-132.
[44].严艳,李卓,李洪权,等.细胞细胞介素-10基因多态性与乙型肝炎病毒感染的关系.世界华人消化杂志,2006,14(36)：3529-3533.
[45].张健,李卫宁,林华.IL-10基因启动子区-592A/C位点多态性与HBV感染转归的关系.现代检验医学杂志,2007,22(3)：81-84.
[46]李艳杰,龙火生,李影,杨公社。单核苷酸多态性的研究进展和应用[J].Journal of Animal Science and Veterinary Medicine;2003;22(4):16-18.