SOCS1/3对TLR3表达和T细胞分化的调控及其在桥本甲状腺炎中的作用
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摘要
目的:探讨细胞信号传导抑制因子1/3(SOCS1、SOCS3,SOCS1/3)对Toll样受体3(TLR3)和T细胞分化的调控及其在桥本甲状腺炎(HT)中的作用。方法:收集已确诊的桥本甲状腺炎患者40例(HT组)及正常体检人群30例(对照组);通过Ficoll密度梯度离心法分离外周血单核细胞(PBMCs),流式细胞术检测调节性T细胞(CD4+CD25+Treg,Treg)、辅助性T细胞17(Th17)及滤泡辅助性T细胞(Tfh),免疫组化法(IHC)检测甲状腺组织中SOCS1/3及TLR3蛋白表达,ELISA检测血浆中SOCS1/3、STAT3蛋白水平,qRT-PCR检测PBMCs中TLR3、SOCS1/3、STAT3、RORγt、Bcl6、Foxp3 mRNA的表达水平。结果:HT组PBMCs中Treg细胞数量降低而Th17细胞、Tfh细胞数量升高(P <0. 05),TLR3、SOCS1/3、Bcl6、RORγt mRNA表达升高,Foxp3、STAT3 mRNA表达降低(P <0. 05); HT组甲状腺组织SOCS1/3蛋白、TLR3蛋白浓度升高(P <0. 05),STAT3蛋白表达降低(P <0. 05)。结论:HT患者SOCS1/3表达升高,可能对HT的TLR3表达及T细胞亚群分化起调控作用。
Objective: To investigate the regulation of SOCS1,SOCS3( SOCS1/3) on Toll like receptors 3( TLR3) and T cell differentiation and its role in Hashimoto's thyroiditis. Methods: Forty patients with HT( HT group) and thirty healthy controls( Control group) were collected. Peripheral blood mononuclear cells( PBMCs) were isolated by ficoll density gradient centrifugation. The protortions of regulatory T cells( CD4+CD25+Treg,Treg),T helper cell 17( Th17) and Follicular helper T cells( Tfh) were analyzed by flow cytometry. The protein expression of SOCS1/3 and STAT3 in the thyroid tissues were detected by immunohistochemistry( IHC). The protein epxression of SOCS1/3 and STAT3 in plasma were detected by ELISA. qRT-PCR was used to detect the mRNA expression level of TLR3,SOCS1/3,STAT3,RORγt,Bcl6,Foxp3. Results: In patients with HT,the proportion of Treg cells was decreased,while the proportion of Th17 cells and Tfh cells were significantly elevated. The mRNA expressions of TLR3,SOCS1/3,Bcl6 and RORγt in PBMCs were increased,while the mRNA expressions of Foxp3 and STAT3 were decreased( P < 0. 05). The expression levels of TLR3 expression and SOCS1/3 protein in thyroid tissue were increased( P < 0. 05),STAT3 protein was decreased( P < 0. 05). Conclusion:SOCS1/3 in HT patients are significantly elevated and may play a role in regulation of TLR3 expression and T cell differentiation.
Objective: To investigate the regulation of SOCS1,SOCS3( SOCS1/3) on Toll like receptors 3( TLR3) and T cell differentiation and its role in Hashimoto's thyroiditis. Methods: Forty patients with HT( HT group) and thirty healthy controls( Control group) were collected. Peripheral blood mononuclear cells( PBMCs) were isolated by ficoll density gradient centrifugation. The protortions of regulatory T cells( CD4+CD25+Treg,Treg),T helper cell 17( Th17) and Follicular helper T cells( Tfh) were analyzed by flow cytometry. The protein expression of SOCS1/3 and STAT3 in the thyroid tissues were detected by immunohistochemistry( IHC). The protein epxression of SOCS1/3 and STAT3 in plasma were detected by ELISA. qRT-PCR was used to detect the mRNA expression level of TLR3,SOCS1/3,STAT3,RORγt,Bcl6,Foxp3. Results: In patients with HT,the proportion of Treg cells was decreased,while the proportion of Th17 cells and Tfh cells were significantly elevated. The mRNA expressions of TLR3,SOCS1/3,Bcl6 and RORγt in PBMCs were increased,while the mRNA expressions of Foxp3 and STAT3 were decreased( P < 0. 05). The expression levels of TLR3 expression and SOCS1/3 protein in thyroid tissue were increased( P < 0. 05),STAT3 protein was decreased( P < 0. 05). Conclusion:SOCS1/3 in HT patients are significantly elevated and may play a role in regulation of TLR3 expression and T cell differentiation.
引文
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[4]Endo TA,Masuhara M,Yokouchi M,et al.A new protein containing an SH2 domain that inhibits JAK kinases[J].Nature,1997,387(6636):921-924.
[5]Jiang M,Zhang WW,Liu P,et al.Dysregulation of SOCS-mediated negative feedback of cytokine signaling in carcinogenesis and its significance in cancer treatment[J].Front Immunol,2017,8:70.
[6]Brunstein CG,Miller JS,Cao Q,et al.Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood:safety profile and detection kinetics[J].Blood,2011,117(3):1061-1070.
[7]Tao JH,Cheng M,Tang JP,et al.Foxp3,regulatory T cell,and autoimmune diseases[J].Inflammation,2017,40(1):328-339.
[8]Wing K,Sakaguchi S.Regulatory T cells exert checks and balances on self tolerance and autoimmunity[J].Nat Immunol,2010,11(1):7-13.
[9]Hsieh CS,Lee HM,Lio CW.Selection of regulatory T cells in the thymus[J].Nat Rev Immunol,2012,12(3):157-167.
[10]Lal G,Zhang N,van der Touw W,et al.Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation[J].JImmunol,2009,182(1):259-273.
[11]孙庆凯,陈占玲,李春华,等.白细胞介素6/转化生长因子-β信号异常在桥本甲状腺炎辅助性T细胞17/调节性T细胞失衡中的作用研究[J].中华内分泌代谢杂志,2015,31(4):320-326.Sun QK,Chen ZL,Li CH,et al.Investigation of the roles of interleukin 6 and transforming growth factorβsignaling in Th17/Treg imbalance of Hashimoto's thyroiditis[J].Chin J Endocrinol Metab,2015,31(4):320-326.
[12]Qiu H,Wu H,Chan V,et al.Transcriptional and epigenetic regulation of follicular T-helper cells and their role in autoimmunity[J].Autoimmunity,2017,50(2):71-81.
[13]Yu D,Rao S,Tsai LM,et al.The transcriptional repressor Bcl-6directs T follicular helper cell lineage commitment[J].Immunity,2009,31(3):457-468.
[14]Choi YS,Yang JA,Crotty S.Dynamic regulation of Bcl6 in follicular helper CD4 T(Tfh)cells[J].Curr Opin Immunol,2013,25(3):366-372.
[15]Dowson C,Simpson N,Duffy L,et al.Innate immunity in systemic sclerosis[J].Curr Rheumatol Rep,2017,19(1):2.
[16]Yoshimura A,Suzuki M,Sakaguchi R,et al.SOCS,Inflammation,and Autoimmunity[J].Front Immunol,2012,3:20.
[17]Harii N,Lewis CJ,Vasko V,et al.Thyrocytes express a functional toll-like receptor 3:overexpression can be induced by viral infection and reversed by phenylmethimazole and is associated with Hashimoto's autoimmune thyroiditis[J].Mol Endocrinol,2005,19(5):1231-1250.