抑制性寡脱氧核苷酸对小鼠CD4~+T细胞转录因子T-bet、STAT4及STAT6的表达及意义
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摘要
目的：探讨体外实验中,抑制性寡脱氧核苷酸(Sup ODN)对小鼠脾脏CD4+T细胞转录因子T-bet、STAT4及STAT6表达的影响。
方法：分离小鼠脾脏淋巴细胞,免疫磁珠阳选法纯化CD4+T细胞,流式细胞仪分析分选纯度,在抗-CD3ε抗体、抗-CD28抗体、IL-12作用下,加入Sup ODN或对照寡脱氧核苷酸(Con ODN)培养72小时后,常规提取核蛋白。Western-blot测定核蛋白中磷酸化的磷酸化信号转导子和转录激动子4(Phosphorylationsignal transducers and ctivators of transcription 4,STAT4)、磷酸化信号转导子和转录激动子6 (Phosphorylationsignal transducers and ctivators of transcription 6,STAT6)和T细胞表达的T盒(T box expressed in T cells, T-bet)蛋白表达。
结果：与Con ODN组和PBS组相比,Sup ODN组中T-bet和pSTAT4的表达水平明显降低(p<0.05),而pSTAT6表达水平明显升高(p<0.05)。
结论：Sup ODN可能通过下调pSTAT4和T-bet的表达,体外抑制小鼠CD4+T细胞向Thl细胞的功能性分化,上调pSTAT6的表达,促进Th2细胞的分化。
Objective:To investigate effect of suppressive oligodeoxy-nucleotides (Sup ODN) on expression of T-bet, pSTAT4 and pSTAT6 of CD4+T splenetic lymphocytes in vitro.
Methods:The splenetic lymphocytes of BALB/c mice were separated and then CD4+cells were purified with immune magnetic CD4+microbeads(positive selection). The purification was examined by FACS. The co-culture of CD4+cel、anti-CD3ε、anti-CD28、IL-12 and Sup ODN or control oligodeoxynucleotides(Con ODN) was performed for 72 hours. The nucleoprotein was extracted with regular procedure. Expression of pSTAT4(phosphorylated pSTAT4), pSTAT6, T-bet in nucleoprotein were detected by Western-blot.
Results:Compared with control ODN and PBS treated group, expression of pSTAT4 and T-bet in Sup ODN treated group decreased significantly (p<0.05), while expression of pSTAT6 in Sup ODN treated group increased significantly (p<0.05).
Conclusion:Sup ODN inhibit Thl differentiation of mice CD4+T cell by down regulate expression of pSTAT4 and T-bet, and promote Th2 differentiation by up regulate expression of pSTAT6.
方法：分离小鼠脾脏淋巴细胞,免疫磁珠阳选法纯化CD4+T细胞,流式细胞仪分析分选纯度,在抗-CD3ε抗体、抗-CD28抗体、IL-12作用下,加入Sup ODN或对照寡脱氧核苷酸(Con ODN)培养72小时后,常规提取核蛋白。Western-blot测定核蛋白中磷酸化的磷酸化信号转导子和转录激动子4(Phosphorylationsignal transducers and ctivators of transcription 4,STAT4)、磷酸化信号转导子和转录激动子6 (Phosphorylationsignal transducers and ctivators of transcription 6,STAT6)和T细胞表达的T盒(T box expressed in T cells, T-bet)蛋白表达。
结果：与Con ODN组和PBS组相比,Sup ODN组中T-bet和pSTAT4的表达水平明显降低(p<0.05),而pSTAT6表达水平明显升高(p<0.05)。
结论：Sup ODN可能通过下调pSTAT4和T-bet的表达,体外抑制小鼠CD4+T细胞向Thl细胞的功能性分化,上调pSTAT6的表达,促进Th2细胞的分化。
Objective:To investigate effect of suppressive oligodeoxy-nucleotides (Sup ODN) on expression of T-bet, pSTAT4 and pSTAT6 of CD4+T splenetic lymphocytes in vitro.
Methods:The splenetic lymphocytes of BALB/c mice were separated and then CD4+cells were purified with immune magnetic CD4+microbeads(positive selection). The purification was examined by FACS. The co-culture of CD4+cel、anti-CD3ε、anti-CD28、IL-12 and Sup ODN or control oligodeoxynucleotides(Con ODN) was performed for 72 hours. The nucleoprotein was extracted with regular procedure. Expression of pSTAT4(phosphorylated pSTAT4), pSTAT6, T-bet in nucleoprotein were detected by Western-blot.
Results:Compared with control ODN and PBS treated group, expression of pSTAT4 and T-bet in Sup ODN treated group decreased significantly (p<0.05), while expression of pSTAT6 in Sup ODN treated group increased significantly (p<0.05).
Conclusion:Sup ODN inhibit Thl differentiation of mice CD4+T cell by down regulate expression of pSTAT4 and T-bet, and promote Th2 differentiation by up regulate expression of pSTAT6.
引文
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[8]Szabo SJ, Kim ST, Costa GL, et al. A novel t ranscription factor, T-bet, directs Thl lineage commitment. Cell,2000,100:655-669.
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[21]Kuzuhara H, Nishiyama S, Minowa N, et al. Protective effects of Soyasapogenol A on liver injury mediated by immune response in a concanavalin A-induced hepatitis model. Eur J Pharmacol,2000,391(1-2): 175-181
[22]Wang J, Zhao Y,Xu Q. Astilbin prevents concanaval in A-induced liver injury by reducing TNF-alpha production and T lymphocytes adhesion. J Pharm Pharmaeol,2004,56(4):495-502
[23]LiuLL, Gong LK, Wang H, et al. Baicalin protects mouse from Concanavalin A-induced liver injury through inhibition of cytokine production and hepatocyte apoptosis. Liver Int,2007,27(4):582-591
[24]Zhao Y, Liu J,Wang J, et al. Fumigaclavine C improves concanavalin A induced liver injury in mice mainly via inhibiting TNF-alpha production and lymphocyte adhesion to extracellular matrices. J Pharm Pharmacol,2004,56(6):775-782
[25]Ohta S, Nakatnuta M, Fukushima M, et al. Beraprost sodium,a prostacyclin(PGI) analogue, ameliorates concanavalin A-induced liver injury in mice. Liver Int,2005,25(5):1061-1068
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[28]Klinman DM, Gursel I, Kliaschik S, et al. Therapeutic potential of oligonucleotides expressing immunosuppressive TTAGGG motifs. Ann N Y Acad Sci,2005,1058:87-95
[29]Shirota H, Gursel I, Gursel M, et al. Suppressive 0 ligodeoxynucleotides protect mice from lethal endotoxic shock. J Immunol,2005; 174(8):4579-4583
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[2]李宁,范学工,陈朝晖,等.CpG-ODN体外抑制乙型肝炎病毒复制的研究.细胞与分子免疫学杂志,2005,21(1)：103-105.
[3]Li N, Fan XG, Chen ZH, et al Inhibition of the hepatitis B virus replication in vitro by an oligodeoxynucleotide containing cytidine-guanosine motifs. Immunol Lett,2006,102(1):60-66.
[4]Klinman DM. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Immunol,2004,4(1):1-10.
[5]Shirota H,Gursel M,Klinman DM. Suppressive oligodeoxynucleotides inhibit Thl differentiation by blocking IFN-gamma-and IL-12-mediated signaling. J Immunol,2004,173(8):5002-5007.
[6]Klinman DM, Gursel I, Klaschik S, et al. Therapeutic Potential of Oligonucleotides Expressing Immunosuppressive TTAGGG Motifs.Ann N Y Acad Sci,2005,1058:87-95.
[7]Dong L, Ito S, Ishii KJ, et al Suppressive oligonucleotides protect against collagen-induced arthritis in mice. Arthritis Rheum,2004,50(5):1686-1689.
[8]Szabo SJ, Kim ST, Costa GL, et al. A novel t ranscription factor, T-bet, directs Thl lineage commitment. Cell,2000,100:655-669.
[9]Hildner KM, Schirmacher P, Atreva I, et al. Targeting of the transcription factor STAT4 by antisense phosphorothioate oligonucleotides suppresses collagen-induced arthritis. J Immunol.2007,178(6):3427-3436.
[10]Murphy KM,Reiner SL.The lineage decisions of helper T cells.Nat Rev Immunol,2002,2(12):933-944.
[11]Ihn H,Yazawa N,Kubo M,et al.Circulating levels of soluble CD30 are increased in patients with localized scleroderma and correlated with serological and clinical features of the disease. J Rheumatol,2000,27(3):698-702
[12]Levy DE, Darnell JE. Stats:transcriptional control and biological impact[J]. NatRev Mol Cell BiO1.2002,3(9):651-662.
[13]Nelms K, Keegan AD, Zamorano J,et al. The IL-4 receptor:signaling mechanisims and biologic fuctions. Annu Immunol.1999,17(1):701-738.
[14]Alessandra BP,Paul BR. JAK-STAT signaling in asthma.Clin Invest.2002, 109(10):1279-1283.
[15]Szabo SJ, Kim ST,Costa GL,et al. A novel transcription factor,T-bet,directs Thl lineage commitment. Cell,2000,100(6):655-669.
[16]Mullen AC, Hilgh FA, Hutchins AS, et al. Role of T-bet in commitment of Thl cells before IL-12-dependent selection. Science,2001,292:1907-1910.
[17]Thomas H, Esther R,Petra A, et al. A genetic basis for IFNγ production and T-bet expression in Humans.The Journal oflmmunology,2005,175 5457-5462。
[18]Finotto S, Neurath MF,Glickman JN,et al. Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science,2002, 295:336-338
[19]Wang ZE,Reiner SL,Zheng S, et al. CD4+effector cells default to the Th2 pathway in interferon gamma-deficient mice infected with Leishmania major. J Exp Med,1994,179(4):1367-1371.
[20]LI SL,DAI XH,F XG,et al.Effect of suppressive oligodeoxynucleotides on the functional differentiation in CD4+Thl lymphocytes in mice in vitro.Journal of Central South University(Medical Sciences),2008,33(12):1089-94
[21]Kuzuhara H, Nishiyama S, Minowa N, et al. Protective effects of Soyasapogenol A on liver injury mediated by immune response in a concanavalin A-induced hepatitis model. Eur J Pharmacol,2000,391(1-2): 175-181
[22]Wang J, Zhao Y,Xu Q. Astilbin prevents concanaval in A-induced liver injury by reducing TNF-alpha production and T lymphocytes adhesion. J Pharm Pharmaeol,2004,56(4):495-502
[23]LiuLL, Gong LK, Wang H, et al. Baicalin protects mouse from Concanavalin A-induced liver injury through inhibition of cytokine production and hepatocyte apoptosis. Liver Int,2007,27(4):582-591
[24]Zhao Y, Liu J,Wang J, et al. Fumigaclavine C improves concanavalin A induced liver injury in mice mainly via inhibiting TNF-alpha production and lymphocyte adhesion to extracellular matrices. J Pharm Pharmacol,2004,56(6):775-782
[25]Ohta S, Nakatnuta M, Fukushima M, et al. Beraprost sodium,a prostacyclin(PGI) analogue, ameliorates concanavalin A-induced liver injury in mice. Liver Int,2005,25(5):1061-1068
[26]Hentze H, Gantner F, Kolb SA,et al. Depletion of hepatic glutathione prevents death receptor-dependent apoptotie and necrotic liver injury in mice. Am J Pathol,2000,156(6):2045-2056
[27]Krig AM, WuT, Weeratna R, et al. Sequence motifs in adnoviral DNA block immune activatin by stimulatory CpG motifs. PNAS,1998,95(21): 12631-12636
[28]Klinman DM, Gursel I, Kliaschik S, et al. Therapeutic potential of oligonucleotides expressing immunosuppressive TTAGGG motifs. Ann N Y Acad Sci,2005,1058:87-95
[29]Shirota H, Gursel I, Gursel M, et al. Suppressive 0 ligodeoxynucleotides protect mice from lethal endotoxic shock. J Immunol,2005; 174(8):4579-4583
[1]Gursel, I.,M. Gursel, H. Yamada, et al.2003. Repet-itive elements inmammalian telomeres suppress bacterial DNA-induced immune activation. J. Immunol.171: 1393-1400.
[2]DE Lange, T.& T. Jacks.1999. For better or worse? Telomerase Inhibition and Cancer Cell 98:273-275.
[3]Blasco, M.A. et al.1999. Telomeres and telomerase.Genes Dev.13:2353-2359.
[4]Zeuner R.A., K.J. Ishii, M.J. Lizak, et al.2002.Reduction of GpG-induced arthritis by suppressive oligodeoxynucleotides. Arthritis Rheum.46:2219-2224.
[5]Yamada, H., I. Gursel, F. Takeshita, et al.2002. Effect of suppressive DNA on CpG-induced immune activation. J. Immunol.169:5590-5594.
[6]Halpern,M.D.& D.S. Pisetsky.1995. In vitro inhibition of murine IFN gamma production by phosphorothioate deoxyguanosine oligomers. Immunopharm 29: 47-52.
[7]Pisetsky, D.S.2000. Inhibition of murine macrophage IL-12 production by natural and synthetic DNA. Clin. Immunol.96:198-204.
[8]Zhu, F.G., C.F. Reich & D.S. Pisetsky.2002. Inhibi-tion of murine macrophage nitric oxide productionby synthetic oligonucleotides. J. Leukoc. Biol.71: 686-694.
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