IL-27基因多态性与东北汉族人哮喘易感性的相关性研究
摘要
目的：利用病例-对照方法探讨研究IL-27p28基因启动子区g.-964A>G,第二外显子区g.2905T>G位点多态性与中国东北汉族人哮喘之间的相关性。方法：通过病例-对照研究,选择病例组和对照组,抽取研究对象的血液标本,基因分型采用基因测序法对SNP位点进行测序,记录每个样本的基因型,计算各位点在哮喘组和对照组中的基因型频率及等位基因频率。Hardy-Weinberg平衡吻合度检验：根据平衡吻合度定律采用Fisher's Exact Test检验计算各多态位点在哮喘组和对照组的预期基因型频率,以比较所观察到的基因型频率和预期的基因型频率之间的差异。确定所选哮喘组和对照组是否可以代表东北汉族群体。基因型与等位基因分布差异检测：运用SPSS17.0软件采用卡方检验比较各多态位点在哮喘组与对照组的基因型与等位基因频率差异,检验多态位点与哮喘的相关性。结果：IL-27p28基因多态位点g.-964A>G采用其互补链进行检测即-964T>C,在哮喘组和对照组显示三种基因型,分别是：T/T、T/C、C/C基因型。基因型频率在哮喘组分别为：0.524、0.238、0.238；在对照组分别为：0.486、0.423、0.091；等位基因T和C的分布频率在哮喘组分别：0.643、0.357;在对照组分别为：0.698、0.302,经x2检验p=0.082、0.477。IL-27p28基因多态位点g.2905T>G,在哮喘组基因型显示为：T/T、T/G基因型,基因型频率分别为：0.833、0.167;在对照组中显示为T/T、T/G、G/G三种基因型,分别为：0.838、0.152、0.010；等位基因T和G的分布频率在哮喘组分别为：0.917、0.083,在对照组分别为：0.914、0.086,经x2检验p=0.880、1.000。结论：IL-27p28基因多态位点-964A>G、2905T>G在中国东北汉族人群中与哮喘无显著相关,但不排除该基因内的其它多态位点与哮喘易感性相关。
Objective:To detect the relationship of IL-27p28 gene polymorphisms in promoter region g.-964A>G and the second exon g.2905T>G with the susceptibility to asthma in northeastern China population. Methods:111 healthy controls were recruited from the general population who took a comprehensive medical examination at northeast region, and asthma patients were recruited from the northeast. Genomic DNA were extracted from the whole blood using the methods of small dosage with DNA extraction reagents. IL27p28 gene was amplified from genomic DNA by polymerase chain reaction method. Then, the fragments containing g.-964A>G, and g.2905T>G were directly sequenced, and the genotypes of these two sites were recorded. The cases and controls were compared by case-control association analysis. Fisher's Exact Test was used to detect deviation from Hardy-Weinberg equilibrium. Genotype and allele frequencies were compared between healthy controls and asthma patients by chi-square test. Results:All genetic variants were in Hardy-Weinberg equilibrium. A/A, A/G, G/G genotypes were detected in g.-964 locus and the genotype frequencies in asthma patients showed: A/A, A/G, G/G was 0.524,0.238,0.238 respectively, in healthy control were 0.486> 0.423、0.091 respectively. Allele frequencies showed:A was 0.643, G was 0.357 in asthma patients,0.698 and 0.302 in healthy control, p value was 0.082 and 0.477 by chi square examination.T/T、T/G、G/G genotypes were detected in 2905T>G locus in healthy controls, but in asthma patients only T/T、T/G genotypes. The genotype frequencies in asthma patients showed:T/T、T/G、G/G was 0.833,0.167,0 respectively, in healthy control were 0.838、0.152、0.010 respectively. Allele frequencies showed:T was 0.917, G was 0.083 in asthma patients,0.914 and 0.086 in healthy control. p value was 0.880 and 0.477 by chi square examination. Conclusion:IL-27p28 gene polymorphisms-964A>G,2905T>A might not be associated with asthma susceptibility in Northeastern Chinese Han population, but does not rule out the possibility that other genes within the polymorphic sites associated with asthma.
Objective:To detect the relationship of IL-27p28 gene polymorphisms in promoter region g.-964A>G and the second exon g.2905T>G with the susceptibility to asthma in northeastern China population. Methods:111 healthy controls were recruited from the general population who took a comprehensive medical examination at northeast region, and asthma patients were recruited from the northeast. Genomic DNA were extracted from the whole blood using the methods of small dosage with DNA extraction reagents. IL27p28 gene was amplified from genomic DNA by polymerase chain reaction method. Then, the fragments containing g.-964A>G, and g.2905T>G were directly sequenced, and the genotypes of these two sites were recorded. The cases and controls were compared by case-control association analysis. Fisher's Exact Test was used to detect deviation from Hardy-Weinberg equilibrium. Genotype and allele frequencies were compared between healthy controls and asthma patients by chi-square test. Results:All genetic variants were in Hardy-Weinberg equilibrium. A/A, A/G, G/G genotypes were detected in g.-964 locus and the genotype frequencies in asthma patients showed: A/A, A/G, G/G was 0.524,0.238,0.238 respectively, in healthy control were 0.486> 0.423、0.091 respectively. Allele frequencies showed:A was 0.643, G was 0.357 in asthma patients,0.698 and 0.302 in healthy control, p value was 0.082 and 0.477 by chi square examination.T/T、T/G、G/G genotypes were detected in 2905T>G locus in healthy controls, but in asthma patients only T/T、T/G genotypes. The genotype frequencies in asthma patients showed:T/T、T/G、G/G was 0.833,0.167,0 respectively, in healthy control were 0.838、0.152、0.010 respectively. Allele frequencies showed:T was 0.917, G was 0.083 in asthma patients,0.914 and 0.086 in healthy control. p value was 0.880 and 0.477 by chi square examination. Conclusion:IL-27p28 gene polymorphisms-964A>G,2905T>A might not be associated with asthma susceptibility in Northeastern Chinese Han population, but does not rule out the possibility that other genes within the polymorphic sites associated with asthma.
引文
[1]Borriello F,et al. B7-1 and.B7-2 have overlapping critical roles in immunoglobulin class switching and germinal center formation. Immunity,1997,6:303-313.
[2]Pflanz S,et al.IL-27,a heterodimeric cytokine composed of EBI3 and p28 induces proliferation of native CD4+T cell.Immunity,2002,16(6):779-790
[3]Poleganov MA, Bachmann M, Pfeilschifter J, et al·Genome-wide analysis displays marked induction of EBI3/IL-27B in IL-18-activated ML derived KG1 cells:critical role of two kappa B binding sites in the human EBI3 promotor. Mol Immunol,2008, 45(10):2869
[4]Wirtz S,et al.EBV-induced gene 3 transcription is induced by TLR signaling in primary dendritic cells via NF-kappa B activation. J Immumol,2005, 174:2814-2824
[5]Hibbert L,et al.IL-27 and IFN-alpha signal via Statl and Stat3 and induce T-Bet and IL-12Rbeta2 in native T cells. J Interferon Cytokine Res,2003,23:513-522
[6]Pflanz S,et al.WSX-1 and glycoprotein 130 constitute a signaltransducting receptor for IL-27.J Immumol,2004,172(4):2225-2231
[7]Kamiya S,et al.An indispensable role for STAT1 in IL-27 induced T-bet expression but not proliferation of native CD4+T cells.J Immuno1,2004,173(6):3871-387.7.
[8]Takeda A, et al.Cutting edge:role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment.J Immunol, 2003,170(10):4886-4890.
[9]Lucas S, et al.IL-27 regulates IL-12 responsiveness of native CD4+T cells through Stat1-dependent and-independent mechanisms. Proc Natl Acad Sci,2003,100(25): 15047-15052.
[10]Morishima N, et al.Augmentation of Effector CD8+T cellgeneration with enhanced granzynte B expression by IL-27.J Immunol,2005,175(3):1686-1693.
[11]Yosimoto T, et al.Induction of IgG2 a class switching in B cells by IL-27.J Im-munol,2004,173(4):2479-2485.
[12]Owaki T, et al.A role for IL-27 in early regulation of Thl differentiation. J Immu nol,2005,175:2191-2200
[13]Owaki T,et al. IL-27 Suppresses CD28-mediated IL-2 production through suppress or of cytokine signaling 3.J Immunol,2006,176:2773-2780
[14]Yoshida H, Miyazaki Y, Wang S, et al.Regulation of defense re-sponses against protozoan infection by interleukin-27 and related cyto-kines·J Biomed Biotechnol, 2007,2007(3):79401
[15]Owaki T, Asakawa M, Morishima N, et al.STAT3 is indispensable to IL-27-mediated cell proliferation but not to IL-27-induced Thl differentiation and suppression of proinflammatory cytokine production.J Immunol,2008,180(5):2903
[16]Miyazaki Y, Shimanoe Y, Wang S,et al.Amelioration of delayed type hypersensitivity responses by IL-27 administration.Biochem Biophys Res Commun, 2008,373(3):397
[17]Villarino A, Hibbert L, Lieberman L, et al·The IL-27R (WSX-1) is required to suppressT cellhyperactivity during infection.Immunity,2003,19(5):645-655
[18]Yoshimura T, TakedaA, Hamano S, et al.Two-sided roles of IL-27:induction of Thl differentiation on naive CD4+T cells versus suppression of proinflammatory cytokine production including IL-23-induced IL-17 on activated CD4+T cells partially through STAT3-dependentmechanism-J Immuno,2006,177(8):5377-5385.
[19]Wang Y, ThorlaciusH. Mast cell-derived tumour necrosis factor-alpha mediates macrophage inflammatory protein-2-induced recruitment of neutrophils in mice[J]. Br J Pharmacol,2005,145(8):1062-1068.
[20]Pflanz S, Timans JC, Cheung J, et al.IL-27, a heterodimeric cytokine composed of Ebi3 and P28 protein, induce proliferration of native CD4+T cells-Immunity,2002, 16(6):779
[21]HamanoS, et al.WSX-1 is required for resistance to Trypanosoma ceruzi infection by regulation of Proinflammatory cytokine production. Inununity,2003, 19:657-667
[22]Rosas LE etal.Interleukin-27R(WSX-1/T-cellcytokinereceptor)gene-deficient mice display enhanced resistance to Leishmania donovani infection but develop severe liver immunopathology. Am J Pathol,2006,168:158-169
[1]PflanzS,TimansJC, CheungJ,Rosa]es R,Kanzler H,Gilbert J,Hibbert L, Churakova T,Travis M, Vaisberg E, Blumenschein WM, Mattson JD, WagnerJL, To W, Zurawski S,MeClanahan TK,GormanDM,Bazan JF,de Waal Malefyt R, RennickD,KasteleinRA.IL-27,a heterodimeric cytokine composed ofEBI3 and P28 protein, induces proliferation naive CD4+T cells. Immunity 2002:16:779-790.
[2]Devergne 0, Hummel M, Koeppen H, LeBeauMM, NathansonEC, KieffE, Birkenbach M.A novel interleukin-12 P40-related protein in duced by latent Ebstein-Barr virus in fection in Blymphocyte.J virol 1996:70:1143-1153.
[3]Poleganov MA, Bachmann M, Pfeilschifter J, et al.Genome-wide analysis displays marked induction of EBI3/IL-27B in IL-18-activated AML-derived KG1 cells:critical role of two kappa B binding sites in the human EBI3 promotor Mol Immunol,2008, 45(10):2869
[4]Devergne O, Hummel M, Koeppen H, et al.A novel interleukin-12p40-related protein induced by latent Epstein-Barr virus infection in lymphocytes·J Virol,1996, 70(2):1143
[5]Devergne O, Coulomb-L'HermineA, Capel F, et al.Expression of Epstein-Barr virus-induced gene 3, an interleukin-12 p40-related molecule, throughout human pregnancy:involvement of syncytiotrophoblasts and extravillous trophoblasts·Am J Pathol,2001,159(5):1763
[6]VILLARINO V, LARKIN J, SARIS CJ, et al.Positive and negative regulation of the IL-27 receptorduring lymphoid cellactivation [J].J Immuno,1 2005,174(12): 7684-7691.
[7]Pflanz S, Hibbert L, Mattson J, et al-WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27·J Immunol,2004,172(4):2225
[8]TakedaA, Hamano S, YamanakaA, et al.Cutting edge:role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Thl commitment (J). J Immunol 2003,170 (10):4886-4890.
[9]Kamiya S, Owaki T, Morishima N, Fukai F, Mizuguchi J, Yoshimoto T.An indispensable role for STAT1 in IL-27-induced T-bet expression but not proliferation of naive CD4+cells.J Immunol 2004;173:3871-3877.
[10]Lucas S, et al.IL-27 regulates IL-12 responsiveness of native CD4+T cells through Stat1-dependent and-independent mechanisms. Proc Natl Acad Sci, 2003,100(25):15047-15052.
[11]Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Thl lineage commitment.Cell 2000:100:655-669.
[12]Mullen AC, High FA, Hutehins AS, Lee HW, Villarino AV, Livingston DM, Kung AL, Cereb N, Yao TP, Yang SY, Reiner SL.Role of T-bet incommitment of THI cells before IL-12-dependent selection.Seience 2001;292:1907-1910.
[13]Zhang DH, Cohn L, Ray P, Bottomly K, Ray A.(1997) Transcription factor GATA-3 is differentially expressed in murine Thl and controls Th2-specific expression of the interleukin-5 gene.J Biol Cheml 997:272:597-603.
[14]ZhengW, Flavell RA.The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells.Cell1997;89:587-596.
[15]Ouyang W, Ranganath SH, Weindel K, Bhattacharya D, Murphy TL, Sha WC, Murphy KM Inhibition of Thl development mediated by GATA-3 through an IL-4-independent mechanism.Immunity 1998:9:745-755.
[16]Owaki T, Asakawa M, Morishima N, et a.l A Role for IL-27 in Early Regulation of Thl Differentiation. J Immuno,1 2005,175(4):2191-2200.
[17]Chen Q, Ghilardi N, Wang H, et a.l Development of Thl-typeimmune responses requires the type I cytokine receptor TCCR.Nature,2000,407:916-920.
[18]YoshidaH, Hamano S, SenaldiG, et a.l WSX-l is required for theinitiation of Thl responses and resistance to L. major infection.Immunity,2001,15(4):569-578.
[19]Artis D, Johnson LM, Joyce K, et a.l Cutting edge:early IL-4 production governs the requirement for IL-27-WSX-1 signaling in the development of protective Thl cytokine responses following Leishmania major infection. J Immunol.2004,172 (8): 4672-4675.
[20]Villarino A, Hibber tL, Lieberman L, et.al The IL-27R (WSX-1)required to suppress T cell hyperactivity during infection. Immunity 2003,19(5):645-655.
[21]OSheaJJ, Paul WE.Regulation of T(H)1 differentiation-controlling the controllers.NatImmunol 2002:3:506-508.
[22]Micallef MJ, Ohtsuki T, Kohno K, Tanabe F, Ushio S, Namba M, Tanimoto T, Torigoe K, Fujii M, Ikeda M, Fukuda S, Kurimoto M. Interferon-gamma-inducing factor enhances T helper 1 cytokine production by stimulated human T cells:synergism with interleukin-12 for interferon-garnma production.Eur J Immunol 1996:26:1647-1651.
[23]Lauwerys BR, Renauld JC, Houssiau FA.Synergistic proliferation and activation of natural killer cells by interleukin 12 and interleukin 18.Cytokine 1999:11:822-302.
[24]Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagne rJ, Zurawski S, LiuY, Abrams JS, Moore KW, Renniek D, de Waa]-Malefyt R, Hannum C, Bazan JF, Kastelein R.A Novel p19 protein engages IL-12 p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12.Immunity2000:13:715-725.
[25]Robinson D, Shibuya K, Mui A, Zonin F, Murphy E, Sana T, Hartley SB, Menon S, Kastelein R, Baxan F, O'GarraA. IGIF does not drive Thl development but synergizes with IL-12 fori nterferon-gamma production and activates IRAK and NFkaPPaB.Immunity 1997;7:571-581.
[26]Ymanaka A, et al.Hyperoduction of Proinflammatory cytokines by WSX-1-deficient NKT cells in concanavalin A-induced hepatitis.J Immunol,2004, 172(6):3590-3596.
[27]Holscher C, et al.The IL-27 Receptor Chain WSX-1 Differentially Regulates Antibacterial Immunity and Survival during Experimental Tuberculosis.J Immunol, 2005,174(6):3534-3544.
[28]Villarino A.et al.IL-27 limits IL-2 production during Thl differentiation.J Immunol.2006,176(1):237-247.
[29]VillarinoAV, HuangE, HunterCA. Understanding the pro-and anti-inflammatory properties of IL-27 [J].J Immunol,2004,173 (2):715-720.
[30]MiyazakiY, InoueH, MatsumuraM,etal. Exacerbation of experimental allergic asthma by augmented Th2 responses inWSX-1-deficientmice[J].J Immunol,2005, 175(4):2401-2407.
[31]Scott P, Natovitz P, Coffman RL, Pearce E, Sher A.Immunoregulation of cutaneous leishmaniasis.T cell lines that transfer protective immunity or exacerbation belong to respond to distinct parasite antigens.J Exp Med 1988; 1168:1675-1684.
[32]Lieberman LA, Hunter CA. The role of cytokines and their signaling pathways in the regulation of immunity to Toxoplasma gondii.Int Rev Immunol 2002;21:373-403.
[33]Reed SG.In vivo administration of recombinant IFN-gamma induces macrophage activation,and prevents acute disease, immune suppression, and death in experimental Trypanosoma cruzi infections.J Immunol 1998;140:4342-4347.
[34]Silva JS, Morrissey PJ, Grabstein KH, Mohler KM, Anderson D, Reed SGInterleukin 10 and interferon gamma regulation of experimental Trypanosoma cruzi infection.J Exp Med 1992;175:169-174.
[35]Bancroft AJ, Else KJ, SyPek JP, Grencis RK.Interleukin-12 promotes a chronic intestinal nematode infection.Eur J Immunol 1997;27:866-870.
[36]Hamano S, Himeno K, Miyazaki Y, lshii K, Yamanaka A, Takeda A, Zhang M, Hisaeda H, Mak TW, Yoshimura A, Yoshida H.WSX-1 is required for resistance to Trypanosoma cruzi infection by regulateon of proinflammatory cytokine production.Immunity 2003:19:657-667.
[37]Holseher C, Holseher A, Ruckerl D, Yoshimoto T, Yoshida H, Mak T, Saris C, Ehlers S.The IL-27 Receptor Chain WSX-1 Differentially Regulates Antibacterial Immunity and Survival during Experimental Tubereulosis.J Immunol 2005:174:3534-3544.
[38]Artis D, Villarino A, Silverman M, He W, Thornton EM, Mu S, Summer S, Covey TM, Huang E, Yoshida H, Koretzky G, Goldschmidt M, Wu GD, deSauvage F, Miller HR, Saris CJ, Scott P, Hunter CA.The IL-27 receptor (wsx-1) is aninhibitor of innate and adaptive elements of type 2 Immunity. J Imrnunol 2004;173:5626-5634
[39]Pearl JE, Khader SA, Solache A, GIImartin L, Ghilardi N, desauvage F, Cooper AM.IL-27 signaling eompromises control of bacterial growth in mycobacteria-infected mice.J Imrnunol 2004;173:7490-7496.
[40]HisadaM, Kamiya S, Fujita K, et a.l Potent antitumor activity of interleukin-27. CancerRes,2004,64(3):1152-1156.
[41]Salcedo R, Stauffer JK, Lincoln E, et a.l IL-27 mediates complete regression of orthotopic primary and metastatic murine neuroblastoma tumors:role for CD8+T cells. J Immuno,1 2004,173(12):7170-7182.
[42]GoldbergR, W ildbaum G, ZoharY, et a.l suppression of ongoing adjuvant-induced arthritis by neutralizing the function of the p28 subunit of IL-27. J Immunol 2004,173(2):1171-1178.
[43]GoldbergR, ZoharY, W ildbaum G, et a.l suppression of ongoing experimental autoimmune encephalomyeliltis by neutralizing the function of the p28 subunit of IL-27. J Immuno.1 2004,173(10):6465-6471.
[44]Shimizu S, Sugiyama N, Masutani K, et a.l Membranous Glomerulonephritis Development with Th2-Type Immune Deviations in MRL/lpr Mice Deficient for IL-27 Receptor (WSX-1). J Immuno,l 2005,175(11):7185-7192.
[45]Larousserie F, PflanzS, Coulomb-L'HermineA, eta.l expression of IL-27 in human Thl-associated granulomatous diseases. Eur J Immuno,1 2004,34(5): 1371-1380.
[46]许雷,杨忠思,白细胞介素-27及其受体的结构与生物学作用.医学分子生物学杂志,2007,4(2)：171-173.
[47]刘彬彬,白细胞介素-27的生物学功能与应用前景.国际内科学杂志,2008,6(6)：345-346.
[2]Pflanz S,et al.IL-27,a heterodimeric cytokine composed of EBI3 and p28 induces proliferation of native CD4+T cell.Immunity,2002,16(6):779-790
[3]Poleganov MA, Bachmann M, Pfeilschifter J, et al·Genome-wide analysis displays marked induction of EBI3/IL-27B in IL-18-activated ML derived KG1 cells:critical role of two kappa B binding sites in the human EBI3 promotor. Mol Immunol,2008, 45(10):2869
[4]Wirtz S,et al.EBV-induced gene 3 transcription is induced by TLR signaling in primary dendritic cells via NF-kappa B activation. J Immumol,2005, 174:2814-2824
[5]Hibbert L,et al.IL-27 and IFN-alpha signal via Statl and Stat3 and induce T-Bet and IL-12Rbeta2 in native T cells. J Interferon Cytokine Res,2003,23:513-522
[6]Pflanz S,et al.WSX-1 and glycoprotein 130 constitute a signaltransducting receptor for IL-27.J Immumol,2004,172(4):2225-2231
[7]Kamiya S,et al.An indispensable role for STAT1 in IL-27 induced T-bet expression but not proliferation of native CD4+T cells.J Immuno1,2004,173(6):3871-387.7.
[8]Takeda A, et al.Cutting edge:role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment.J Immunol, 2003,170(10):4886-4890.
[9]Lucas S, et al.IL-27 regulates IL-12 responsiveness of native CD4+T cells through Stat1-dependent and-independent mechanisms. Proc Natl Acad Sci,2003,100(25): 15047-15052.
[10]Morishima N, et al.Augmentation of Effector CD8+T cellgeneration with enhanced granzynte B expression by IL-27.J Immunol,2005,175(3):1686-1693.
[11]Yosimoto T, et al.Induction of IgG2 a class switching in B cells by IL-27.J Im-munol,2004,173(4):2479-2485.
[12]Owaki T, et al.A role for IL-27 in early regulation of Thl differentiation. J Immu nol,2005,175:2191-2200
[13]Owaki T,et al. IL-27 Suppresses CD28-mediated IL-2 production through suppress or of cytokine signaling 3.J Immunol,2006,176:2773-2780
[14]Yoshida H, Miyazaki Y, Wang S, et al.Regulation of defense re-sponses against protozoan infection by interleukin-27 and related cyto-kines·J Biomed Biotechnol, 2007,2007(3):79401
[15]Owaki T, Asakawa M, Morishima N, et al.STAT3 is indispensable to IL-27-mediated cell proliferation but not to IL-27-induced Thl differentiation and suppression of proinflammatory cytokine production.J Immunol,2008,180(5):2903
[16]Miyazaki Y, Shimanoe Y, Wang S,et al.Amelioration of delayed type hypersensitivity responses by IL-27 administration.Biochem Biophys Res Commun, 2008,373(3):397
[17]Villarino A, Hibbert L, Lieberman L, et al·The IL-27R (WSX-1) is required to suppressT cellhyperactivity during infection.Immunity,2003,19(5):645-655
[18]Yoshimura T, TakedaA, Hamano S, et al.Two-sided roles of IL-27:induction of Thl differentiation on naive CD4+T cells versus suppression of proinflammatory cytokine production including IL-23-induced IL-17 on activated CD4+T cells partially through STAT3-dependentmechanism-J Immuno,2006,177(8):5377-5385.
[19]Wang Y, ThorlaciusH. Mast cell-derived tumour necrosis factor-alpha mediates macrophage inflammatory protein-2-induced recruitment of neutrophils in mice[J]. Br J Pharmacol,2005,145(8):1062-1068.
[20]Pflanz S, Timans JC, Cheung J, et al.IL-27, a heterodimeric cytokine composed of Ebi3 and P28 protein, induce proliferration of native CD4+T cells-Immunity,2002, 16(6):779
[21]HamanoS, et al.WSX-1 is required for resistance to Trypanosoma ceruzi infection by regulation of Proinflammatory cytokine production. Inununity,2003, 19:657-667
[22]Rosas LE etal.Interleukin-27R(WSX-1/T-cellcytokinereceptor)gene-deficient mice display enhanced resistance to Leishmania donovani infection but develop severe liver immunopathology. Am J Pathol,2006,168:158-169
[1]PflanzS,TimansJC, CheungJ,Rosa]es R,Kanzler H,Gilbert J,Hibbert L, Churakova T,Travis M, Vaisberg E, Blumenschein WM, Mattson JD, WagnerJL, To W, Zurawski S,MeClanahan TK,GormanDM,Bazan JF,de Waal Malefyt R, RennickD,KasteleinRA.IL-27,a heterodimeric cytokine composed ofEBI3 and P28 protein, induces proliferation naive CD4+T cells. Immunity 2002:16:779-790.
[2]Devergne 0, Hummel M, Koeppen H, LeBeauMM, NathansonEC, KieffE, Birkenbach M.A novel interleukin-12 P40-related protein in duced by latent Ebstein-Barr virus in fection in Blymphocyte.J virol 1996:70:1143-1153.
[3]Poleganov MA, Bachmann M, Pfeilschifter J, et al.Genome-wide analysis displays marked induction of EBI3/IL-27B in IL-18-activated AML-derived KG1 cells:critical role of two kappa B binding sites in the human EBI3 promotor Mol Immunol,2008, 45(10):2869
[4]Devergne O, Hummel M, Koeppen H, et al.A novel interleukin-12p40-related protein induced by latent Epstein-Barr virus infection in lymphocytes·J Virol,1996, 70(2):1143
[5]Devergne O, Coulomb-L'HermineA, Capel F, et al.Expression of Epstein-Barr virus-induced gene 3, an interleukin-12 p40-related molecule, throughout human pregnancy:involvement of syncytiotrophoblasts and extravillous trophoblasts·Am J Pathol,2001,159(5):1763
[6]VILLARINO V, LARKIN J, SARIS CJ, et al.Positive and negative regulation of the IL-27 receptorduring lymphoid cellactivation [J].J Immuno,1 2005,174(12): 7684-7691.
[7]Pflanz S, Hibbert L, Mattson J, et al-WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27·J Immunol,2004,172(4):2225
[8]TakedaA, Hamano S, YamanakaA, et al.Cutting edge:role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Thl commitment (J). J Immunol 2003,170 (10):4886-4890.
[9]Kamiya S, Owaki T, Morishima N, Fukai F, Mizuguchi J, Yoshimoto T.An indispensable role for STAT1 in IL-27-induced T-bet expression but not proliferation of naive CD4+cells.J Immunol 2004;173:3871-3877.
[10]Lucas S, et al.IL-27 regulates IL-12 responsiveness of native CD4+T cells through Stat1-dependent and-independent mechanisms. Proc Natl Acad Sci, 2003,100(25):15047-15052.
[11]Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Thl lineage commitment.Cell 2000:100:655-669.
[12]Mullen AC, High FA, Hutehins AS, Lee HW, Villarino AV, Livingston DM, Kung AL, Cereb N, Yao TP, Yang SY, Reiner SL.Role of T-bet incommitment of THI cells before IL-12-dependent selection.Seience 2001;292:1907-1910.
[13]Zhang DH, Cohn L, Ray P, Bottomly K, Ray A.(1997) Transcription factor GATA-3 is differentially expressed in murine Thl and controls Th2-specific expression of the interleukin-5 gene.J Biol Cheml 997:272:597-603.
[14]ZhengW, Flavell RA.The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells.Cell1997;89:587-596.
[15]Ouyang W, Ranganath SH, Weindel K, Bhattacharya D, Murphy TL, Sha WC, Murphy KM Inhibition of Thl development mediated by GATA-3 through an IL-4-independent mechanism.Immunity 1998:9:745-755.
[16]Owaki T, Asakawa M, Morishima N, et a.l A Role for IL-27 in Early Regulation of Thl Differentiation. J Immuno,1 2005,175(4):2191-2200.
[17]Chen Q, Ghilardi N, Wang H, et a.l Development of Thl-typeimmune responses requires the type I cytokine receptor TCCR.Nature,2000,407:916-920.
[18]YoshidaH, Hamano S, SenaldiG, et a.l WSX-l is required for theinitiation of Thl responses and resistance to L. major infection.Immunity,2001,15(4):569-578.
[19]Artis D, Johnson LM, Joyce K, et a.l Cutting edge:early IL-4 production governs the requirement for IL-27-WSX-1 signaling in the development of protective Thl cytokine responses following Leishmania major infection. J Immunol.2004,172 (8): 4672-4675.
[20]Villarino A, Hibber tL, Lieberman L, et.al The IL-27R (WSX-1)required to suppress T cell hyperactivity during infection. Immunity 2003,19(5):645-655.
[21]OSheaJJ, Paul WE.Regulation of T(H)1 differentiation-controlling the controllers.NatImmunol 2002:3:506-508.
[22]Micallef MJ, Ohtsuki T, Kohno K, Tanabe F, Ushio S, Namba M, Tanimoto T, Torigoe K, Fujii M, Ikeda M, Fukuda S, Kurimoto M. Interferon-gamma-inducing factor enhances T helper 1 cytokine production by stimulated human T cells:synergism with interleukin-12 for interferon-garnma production.Eur J Immunol 1996:26:1647-1651.
[23]Lauwerys BR, Renauld JC, Houssiau FA.Synergistic proliferation and activation of natural killer cells by interleukin 12 and interleukin 18.Cytokine 1999:11:822-302.
[24]Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagne rJ, Zurawski S, LiuY, Abrams JS, Moore KW, Renniek D, de Waa]-Malefyt R, Hannum C, Bazan JF, Kastelein R.A Novel p19 protein engages IL-12 p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12.Immunity2000:13:715-725.
[25]Robinson D, Shibuya K, Mui A, Zonin F, Murphy E, Sana T, Hartley SB, Menon S, Kastelein R, Baxan F, O'GarraA. IGIF does not drive Thl development but synergizes with IL-12 fori nterferon-gamma production and activates IRAK and NFkaPPaB.Immunity 1997;7:571-581.
[26]Ymanaka A, et al.Hyperoduction of Proinflammatory cytokines by WSX-1-deficient NKT cells in concanavalin A-induced hepatitis.J Immunol,2004, 172(6):3590-3596.
[27]Holscher C, et al.The IL-27 Receptor Chain WSX-1 Differentially Regulates Antibacterial Immunity and Survival during Experimental Tuberculosis.J Immunol, 2005,174(6):3534-3544.
[28]Villarino A.et al.IL-27 limits IL-2 production during Thl differentiation.J Immunol.2006,176(1):237-247.
[29]VillarinoAV, HuangE, HunterCA. Understanding the pro-and anti-inflammatory properties of IL-27 [J].J Immunol,2004,173 (2):715-720.
[30]MiyazakiY, InoueH, MatsumuraM,etal. Exacerbation of experimental allergic asthma by augmented Th2 responses inWSX-1-deficientmice[J].J Immunol,2005, 175(4):2401-2407.
[31]Scott P, Natovitz P, Coffman RL, Pearce E, Sher A.Immunoregulation of cutaneous leishmaniasis.T cell lines that transfer protective immunity or exacerbation belong to respond to distinct parasite antigens.J Exp Med 1988; 1168:1675-1684.
[32]Lieberman LA, Hunter CA. The role of cytokines and their signaling pathways in the regulation of immunity to Toxoplasma gondii.Int Rev Immunol 2002;21:373-403.
[33]Reed SG.In vivo administration of recombinant IFN-gamma induces macrophage activation,and prevents acute disease, immune suppression, and death in experimental Trypanosoma cruzi infections.J Immunol 1998;140:4342-4347.
[34]Silva JS, Morrissey PJ, Grabstein KH, Mohler KM, Anderson D, Reed SGInterleukin 10 and interferon gamma regulation of experimental Trypanosoma cruzi infection.J Exp Med 1992;175:169-174.
[35]Bancroft AJ, Else KJ, SyPek JP, Grencis RK.Interleukin-12 promotes a chronic intestinal nematode infection.Eur J Immunol 1997;27:866-870.
[36]Hamano S, Himeno K, Miyazaki Y, lshii K, Yamanaka A, Takeda A, Zhang M, Hisaeda H, Mak TW, Yoshimura A, Yoshida H.WSX-1 is required for resistance to Trypanosoma cruzi infection by regulateon of proinflammatory cytokine production.Immunity 2003:19:657-667.
[37]Holseher C, Holseher A, Ruckerl D, Yoshimoto T, Yoshida H, Mak T, Saris C, Ehlers S.The IL-27 Receptor Chain WSX-1 Differentially Regulates Antibacterial Immunity and Survival during Experimental Tubereulosis.J Immunol 2005:174:3534-3544.
[38]Artis D, Villarino A, Silverman M, He W, Thornton EM, Mu S, Summer S, Covey TM, Huang E, Yoshida H, Koretzky G, Goldschmidt M, Wu GD, deSauvage F, Miller HR, Saris CJ, Scott P, Hunter CA.The IL-27 receptor (wsx-1) is aninhibitor of innate and adaptive elements of type 2 Immunity. J Imrnunol 2004;173:5626-5634
[39]Pearl JE, Khader SA, Solache A, GIImartin L, Ghilardi N, desauvage F, Cooper AM.IL-27 signaling eompromises control of bacterial growth in mycobacteria-infected mice.J Imrnunol 2004;173:7490-7496.
[40]HisadaM, Kamiya S, Fujita K, et a.l Potent antitumor activity of interleukin-27. CancerRes,2004,64(3):1152-1156.
[41]Salcedo R, Stauffer JK, Lincoln E, et a.l IL-27 mediates complete regression of orthotopic primary and metastatic murine neuroblastoma tumors:role for CD8+T cells. J Immuno,1 2004,173(12):7170-7182.
[42]GoldbergR, W ildbaum G, ZoharY, et a.l suppression of ongoing adjuvant-induced arthritis by neutralizing the function of the p28 subunit of IL-27. J Immunol 2004,173(2):1171-1178.
[43]GoldbergR, ZoharY, W ildbaum G, et a.l suppression of ongoing experimental autoimmune encephalomyeliltis by neutralizing the function of the p28 subunit of IL-27. J Immuno.1 2004,173(10):6465-6471.
[44]Shimizu S, Sugiyama N, Masutani K, et a.l Membranous Glomerulonephritis Development with Th2-Type Immune Deviations in MRL/lpr Mice Deficient for IL-27 Receptor (WSX-1). J Immuno,l 2005,175(11):7185-7192.
[45]Larousserie F, PflanzS, Coulomb-L'HermineA, eta.l expression of IL-27 in human Thl-associated granulomatous diseases. Eur J Immuno,1 2004,34(5): 1371-1380.
[46]许雷,杨忠思,白细胞介素-27及其受体的结构与生物学作用.医学分子生物学杂志,2007,4(2)：171-173.
[47]刘彬彬,白细胞介素-27的生物学功能与应用前景.国际内科学杂志,2008,6(6)：345-346.