转录因子Egr2/Egr3的生物学作用及与自身免疫性疾病的相关性
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摘要
早期生长反应因子Egr,属于即刻反应因子,其家族成员包括Egr1、Egr2、Egr3、Egr4。该家族主要参与调节细胞的生长、分化和凋亡等过程。现已发现,Egr2/Egr3不仅影响T/B细胞的增殖分化,也与多条信号通路如JAK/STAT、NF-κB等有交叉点。Egr2和Egr3与多种自身免疫性疾病的发生密切相关,如系统性红斑狼疮、硬皮病等。Egr2/Egr3有可能成为治疗自身免疫性疾病的新靶点。文章就Egr2/Egr3的生物学作用及与自身免疫性疾病相关性的研究进展进行综述。
Early growth response protein( Egr) belongs to the immediate response factor,whose family members include Egr1,Egr2,Egr3 and Egr4. The Egr protein is mainly involved in the growth,differentiation and apoptosis of cells. It is reported the Egr2/Egr3 protein can not only effect the T/B cell's proliferation and differentiation,but also participate in multiple signaling pathways,such as JAK/STAT and NF-κB). With the in-depth study,it is found that Egr2 and Egr3 have an indispensable relationship with the occurrence of various autoimmune diseases,including Systemic Lupus Erythematosus,Scleroderma,etc. Therefore,Egr2 and Egr3 may be a potential therapy target for autoimmune diseases. This paper reviews the biological effects of Egr2/Egr3 and its research progress in relation to autoimmune diseases.
Early growth response protein( Egr) belongs to the immediate response factor,whose family members include Egr1,Egr2,Egr3 and Egr4. The Egr protein is mainly involved in the growth,differentiation and apoptosis of cells. It is reported the Egr2/Egr3 protein can not only effect the T/B cell's proliferation and differentiation,but also participate in multiple signaling pathways,such as JAK/STAT and NF-κB). With the in-depth study,it is found that Egr2 and Egr3 have an indispensable relationship with the occurrence of various autoimmune diseases,including Systemic Lupus Erythematosus,Scleroderma,etc. Therefore,Egr2 and Egr3 may be a potential therapy target for autoimmune diseases. This paper reviews the biological effects of Egr2/Egr3 and its research progress in relation to autoimmune diseases.
引文
[1]孙小霞,张颖,辛晓燕.EGR转录因子在肿瘤中的研究进展[J].现代肿瘤医学,2017,25(4):654-657.
[2]周鑫昀,陈惠,沈立松.自身免疫性疾病新型自身抗体研究进展[J].检验医学,2017,32(6):543-548.
[3]Tao JH,Cheng M,Tang JP,et al.Foxp3,Regulatory T Cell,and Autoimmune Diseases[J].Inflammation,2017,40(1):328-339.
[4]Ellis JS,Braley-Mullen H.Mechanisms by which B cells and regulatory T cells influence development of murine organ-specific autoimmune diseases[J].J Clin Med,2017,6(2):13-29.
[5]文海平,周红.白细胞介素-1受体相关激酶家族与自身免疫性疾病[J].医学研究生学报,2011,24(1):78-81.
[6]Taefehshokr S,Key YA,Khakpour M,et al.Early growth response 2 and Egr3 are unique regulators in immune system[J].Cent Eur J Immunol,2017,42(2):205-209.
[7]Zhang M,Wang Y,Wang JS,et al.The roles of Egr-2 in autoimmune diseases.[J].Inflammation,2015,38(3):972-977.
[8]Park HJ,Kim DH,Lim SH,et al.Insights into the role of follicular helper T cells in autoimmunity[J].Immune Netw,2014,14(1):21-29.
[9]de Valle E,Grigoriadis G,O'Reilly LA,et al.NFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells[J].J Exp Med,2016,213(4):621-641.
[10]O'Donovan KJ,Tourtellotte WG,Millbrandt J,et al.The EGR family of transcription regulatory factors:progress at the interface of molecular and systems neuroscience[J].Trends Neurosci,1999,22(4):167-173.
[11]Patwardhan S,Gashler A,Siegel MG,et al.EGR3,a novel member of the Egr family of gene encoding immediate-early transcription factors[J].Oncogene,1991,6(6):917-928.
[12]Morita K,Okamura T,Sumitomo S,et al.Emerging roles of Egr2and Egr3 in the control of systemic autoimmunity[J].Rheumatology,2016,55(suppl 2):ii76-ii81.
[13]Okamura T,Sumitomo S,Morita K,et al.TGF-β3-expressing CD4+CD25-LAG3+regulatory T cells control humoral immune responses[J].Nat Commun,2015,6(1):6326-6329.
[14]Bhattacharyya S,Wu M,Fang F,et al.Early growth response transcription factors:key mediators of fibrosis and novel targets for anti-fibrotic therapy[J].Matrix Biol,2011,30(4):235-242.
[15]Fang F,Shangguan AJ,Kelly K,et al.Early Growth Response 3(Egr-3)Is Induced by Transforming Growth Factor-b and Regulates Fibrogenic Responses[J].Am J Pathol,2013,183(4):1197-1208.
[16]Bae CJ,Jeong J,Saintjeannet JP.A novel function for Egr4 in posterior hindbrain development[J].Sci Rep,2015,5:7750-7760.
[17]Miao T,Alj S,Singh R,et al.Egr2 and 3 control adaptive immune responses by temporally uncoupling expansion from T cell differentiation[J].J Exp Med,2017,214(6):1787-1808.
[18]Mages HW,Baag R,Steiner B,et al.Utilization of an NF-AT pbinding promoter element for Egr-3 expression in T cells but not fibroblasts provides a molecular model for the lymphoid cell-specific effect of cyclosporin[J].A Mol Cell Biol,1998,18(12):7157-7165.
[19]Rengarajan J,Mittelstadt PR,Mages HW,et al.Sequential involvement of NFAT and Egr transcription factors in Fas L regulation[J].Immunity,2000,12(3):293-300.
[20]马彪,逄越,王旭,等.Pax5对B细胞分化发育调控作用的研究进展[J].免疫学杂志,2012,28(7):624-627.
[21]任文汇,王春梅,李楠.Notch信号通路在B细胞分化发育以及B细胞淋巴瘤中作用的研究进展[J].中国肿瘤生物治疗杂志,2016,23(2):282-286.
[22]Li S,Miao T,Sebastian M,et al.The transcription factors Egr2and Egr3 are essential for the control of inflammation and antigeninduced proliferation of B and T cells[J].Immunity,2012,37(4),685-696.
[23]Tamiya T,Kashiwagi I,Takahashi R,et al.Suppressors of cytokine signaling(SOCS)proteins and JAK/STAT pathways:regulation of T-cell inflammation by SOCS1 and SOCS3[J].Arterioscler Thromb Vasc Biol,2011,31(5):980-985.
[24]Miah MA,Byeon SE,Ahmed MS,et al.Egr2 induced during DC development acts as an intrinsic negative regulator of DC immunogenicity[J].Eur J Immunol,2013,43(9):2484-2496.
[25]Kershaw NJ,Murphy JM,Lucet IS,et al.Regulation of Janus kinases by SOCS proteins[J].Biochem Soc Trans,2013,41(4):1042-1047.
[26]李敏利,朱人敏.细胞因子信号转导抑制蛋白在JAK/STAT信号通路中的负反馈调节作用[J].医学研究生学报,2009,22(3):329-332.
[27]Lu L,Ye X,Yao Q,et al.Egr2 enhances insulin resistance via JAK2/STAT3/S-OCS-1 pathway in Hep G2 cells treated withpalmitate[J].Gen Comp Endocrinol,2017,260:25-31.
[28]Schraml BU,Hildner K,Ise W,et al.The AP-1 transcription factor Batf controls T(H)17 differentiation[J].Nature,2009,460(7253):405-409.
[29]Sumimoto S,Fujio K,Okamura T,et al.Egr2 and Egr3 are the unique regulators for systemic autoimmunity[J].Proc Natl Acad Sci USA,2016,113(50):E8131-E8140.
[30]Wieland GD,Nehmann N,Muller D,et al,Early growth response proteins EGR-4 and EGR-3 interact with immune inflammatory mediators NF-κB p50 and p65[J].J Cell Sci,2005,118(14):3203-3212.
[31]Nafez S,Oikawa K,Odero GL,et al.Early growth response 2(Egr-2)expression is triggered by NF-κB activation[J].Mol Cell Neurosci,2015,64:95-103.
[32]Butt C,Lim S,Greenwood C,et al.VEGF,FGF1,FGF2 and EGF gene polymorphisms and psoriatic arthritis[J].BMC Musculoskelet Disord,2007,4:1-7.
[33]Suehiro J,Hamakubo T,Kodama T,et al.Vascular endothelial growth factor activation of endothelial cells is mediated by early growth response-3[J].Blood,2010,115(12):2320-2532.
[34]兰生辉.EGFR信号通路通过Egr2促进骨祖细胞增殖并抑制骨祖细胞凋亡的实验性研究[D].华中科技大学,2012.
[35]中华医学会风湿病学分会.类风湿关节炎诊断及治疗指南[J].中华风湿病学志,2010,14(4):265-270.
[36]Kumar KR,Li L,Yan M et al.Regulation of B cell tolerance by the lupus susceptibility gene Ly108[J].Science,2006,312(5780):1665-1669.
[37]Kearney SJ,Delgado C,Eshleman EM,et al.Type I IFNs downregulate myeloid cell IFN-γreceptor by inducing recruitment of an early growth response 3/NGFI-A binding protein 1 complex that silences ifngr1 transcription[J].J Immunol,2013,191(6):3384-3392.
[38]Liu M,Wu W,Sun X,et al.New insights into CD4(+)T cell abnormalities in systemic sclerosis[J].Cytokine Growth Factor Rev,2016,28:31-36.
[39]Yang X,Yang J,Xing X,et al.Increased frequency of Th17cells in systemic sclerosis is related to disease activity and collagen overproduction[J].Arthritis Res Therapy,2014,16(1):1-11.
[40]Miao T,Raymond M,Bhullar P,et al.Early Growth Response Gene-2 Controls IL-17 Expression and Th17 Differentiation[J].J Immunol,2013,190(1):58-65.
[41]Fang F,Shangguan AJ,Kelly K,et al.Early Growth Response 3(Egr-3)Is Induced by Transforming Growth Factor-βand Regulates Fibrogenic Responses[J].Am J Pathol,2013,183(4):1197-1208.
[42]苑杰,江沛,吕佩源,等.细胞自噬与疾病发生发展的关系及作为治疗靶点的研究进展[J].医学研究生学报,2018,31(1):88-91.
[2]周鑫昀,陈惠,沈立松.自身免疫性疾病新型自身抗体研究进展[J].检验医学,2017,32(6):543-548.
[3]Tao JH,Cheng M,Tang JP,et al.Foxp3,Regulatory T Cell,and Autoimmune Diseases[J].Inflammation,2017,40(1):328-339.
[4]Ellis JS,Braley-Mullen H.Mechanisms by which B cells and regulatory T cells influence development of murine organ-specific autoimmune diseases[J].J Clin Med,2017,6(2):13-29.
[5]文海平,周红.白细胞介素-1受体相关激酶家族与自身免疫性疾病[J].医学研究生学报,2011,24(1):78-81.
[6]Taefehshokr S,Key YA,Khakpour M,et al.Early growth response 2 and Egr3 are unique regulators in immune system[J].Cent Eur J Immunol,2017,42(2):205-209.
[7]Zhang M,Wang Y,Wang JS,et al.The roles of Egr-2 in autoimmune diseases.[J].Inflammation,2015,38(3):972-977.
[8]Park HJ,Kim DH,Lim SH,et al.Insights into the role of follicular helper T cells in autoimmunity[J].Immune Netw,2014,14(1):21-29.
[9]de Valle E,Grigoriadis G,O'Reilly LA,et al.NFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells[J].J Exp Med,2016,213(4):621-641.
[10]O'Donovan KJ,Tourtellotte WG,Millbrandt J,et al.The EGR family of transcription regulatory factors:progress at the interface of molecular and systems neuroscience[J].Trends Neurosci,1999,22(4):167-173.
[11]Patwardhan S,Gashler A,Siegel MG,et al.EGR3,a novel member of the Egr family of gene encoding immediate-early transcription factors[J].Oncogene,1991,6(6):917-928.
[12]Morita K,Okamura T,Sumitomo S,et al.Emerging roles of Egr2and Egr3 in the control of systemic autoimmunity[J].Rheumatology,2016,55(suppl 2):ii76-ii81.
[13]Okamura T,Sumitomo S,Morita K,et al.TGF-β3-expressing CD4+CD25-LAG3+regulatory T cells control humoral immune responses[J].Nat Commun,2015,6(1):6326-6329.
[14]Bhattacharyya S,Wu M,Fang F,et al.Early growth response transcription factors:key mediators of fibrosis and novel targets for anti-fibrotic therapy[J].Matrix Biol,2011,30(4):235-242.
[15]Fang F,Shangguan AJ,Kelly K,et al.Early Growth Response 3(Egr-3)Is Induced by Transforming Growth Factor-b and Regulates Fibrogenic Responses[J].Am J Pathol,2013,183(4):1197-1208.
[16]Bae CJ,Jeong J,Saintjeannet JP.A novel function for Egr4 in posterior hindbrain development[J].Sci Rep,2015,5:7750-7760.
[17]Miao T,Alj S,Singh R,et al.Egr2 and 3 control adaptive immune responses by temporally uncoupling expansion from T cell differentiation[J].J Exp Med,2017,214(6):1787-1808.
[18]Mages HW,Baag R,Steiner B,et al.Utilization of an NF-AT pbinding promoter element for Egr-3 expression in T cells but not fibroblasts provides a molecular model for the lymphoid cell-specific effect of cyclosporin[J].A Mol Cell Biol,1998,18(12):7157-7165.
[19]Rengarajan J,Mittelstadt PR,Mages HW,et al.Sequential involvement of NFAT and Egr transcription factors in Fas L regulation[J].Immunity,2000,12(3):293-300.
[20]马彪,逄越,王旭,等.Pax5对B细胞分化发育调控作用的研究进展[J].免疫学杂志,2012,28(7):624-627.
[21]任文汇,王春梅,李楠.Notch信号通路在B细胞分化发育以及B细胞淋巴瘤中作用的研究进展[J].中国肿瘤生物治疗杂志,2016,23(2):282-286.
[22]Li S,Miao T,Sebastian M,et al.The transcription factors Egr2and Egr3 are essential for the control of inflammation and antigeninduced proliferation of B and T cells[J].Immunity,2012,37(4),685-696.
[23]Tamiya T,Kashiwagi I,Takahashi R,et al.Suppressors of cytokine signaling(SOCS)proteins and JAK/STAT pathways:regulation of T-cell inflammation by SOCS1 and SOCS3[J].Arterioscler Thromb Vasc Biol,2011,31(5):980-985.
[24]Miah MA,Byeon SE,Ahmed MS,et al.Egr2 induced during DC development acts as an intrinsic negative regulator of DC immunogenicity[J].Eur J Immunol,2013,43(9):2484-2496.
[25]Kershaw NJ,Murphy JM,Lucet IS,et al.Regulation of Janus kinases by SOCS proteins[J].Biochem Soc Trans,2013,41(4):1042-1047.
[26]李敏利,朱人敏.细胞因子信号转导抑制蛋白在JAK/STAT信号通路中的负反馈调节作用[J].医学研究生学报,2009,22(3):329-332.
[27]Lu L,Ye X,Yao Q,et al.Egr2 enhances insulin resistance via JAK2/STAT3/S-OCS-1 pathway in Hep G2 cells treated withpalmitate[J].Gen Comp Endocrinol,2017,260:25-31.
[28]Schraml BU,Hildner K,Ise W,et al.The AP-1 transcription factor Batf controls T(H)17 differentiation[J].Nature,2009,460(7253):405-409.
[29]Sumimoto S,Fujio K,Okamura T,et al.Egr2 and Egr3 are the unique regulators for systemic autoimmunity[J].Proc Natl Acad Sci USA,2016,113(50):E8131-E8140.
[30]Wieland GD,Nehmann N,Muller D,et al,Early growth response proteins EGR-4 and EGR-3 interact with immune inflammatory mediators NF-κB p50 and p65[J].J Cell Sci,2005,118(14):3203-3212.
[31]Nafez S,Oikawa K,Odero GL,et al.Early growth response 2(Egr-2)expression is triggered by NF-κB activation[J].Mol Cell Neurosci,2015,64:95-103.
[32]Butt C,Lim S,Greenwood C,et al.VEGF,FGF1,FGF2 and EGF gene polymorphisms and psoriatic arthritis[J].BMC Musculoskelet Disord,2007,4:1-7.
[33]Suehiro J,Hamakubo T,Kodama T,et al.Vascular endothelial growth factor activation of endothelial cells is mediated by early growth response-3[J].Blood,2010,115(12):2320-2532.
[34]兰生辉.EGFR信号通路通过Egr2促进骨祖细胞增殖并抑制骨祖细胞凋亡的实验性研究[D].华中科技大学,2012.
[35]中华医学会风湿病学分会.类风湿关节炎诊断及治疗指南[J].中华风湿病学志,2010,14(4):265-270.
[36]Kumar KR,Li L,Yan M et al.Regulation of B cell tolerance by the lupus susceptibility gene Ly108[J].Science,2006,312(5780):1665-1669.
[37]Kearney SJ,Delgado C,Eshleman EM,et al.Type I IFNs downregulate myeloid cell IFN-γreceptor by inducing recruitment of an early growth response 3/NGFI-A binding protein 1 complex that silences ifngr1 transcription[J].J Immunol,2013,191(6):3384-3392.
[38]Liu M,Wu W,Sun X,et al.New insights into CD4(+)T cell abnormalities in systemic sclerosis[J].Cytokine Growth Factor Rev,2016,28:31-36.
[39]Yang X,Yang J,Xing X,et al.Increased frequency of Th17cells in systemic sclerosis is related to disease activity and collagen overproduction[J].Arthritis Res Therapy,2014,16(1):1-11.
[40]Miao T,Raymond M,Bhullar P,et al.Early Growth Response Gene-2 Controls IL-17 Expression and Th17 Differentiation[J].J Immunol,2013,190(1):58-65.
[41]Fang F,Shangguan AJ,Kelly K,et al.Early Growth Response 3(Egr-3)Is Induced by Transforming Growth Factor-βand Regulates Fibrogenic Responses[J].Am J Pathol,2013,183(4):1197-1208.
[42]苑杰,江沛,吕佩源,等.细胞自噬与疾病发生发展的关系及作为治疗靶点的研究进展[J].医学研究生学报,2018,31(1):88-91.