组蛋白H2A去泛素化酶MYSM1抑制骨髓来源树突状细胞的抗原提呈功能及炎性细胞因子的分泌
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摘要
目的研究组蛋白H2A去泛素化酶Myb样SWIRM和MPN结构域1(MYSM1)对骨髓来源树突状细胞(BMDC)吞噬、抗原提呈、炎性细胞因子mRNA水平的影响。方法分离小鼠的骨髓细胞,在体外联合粒细胞巨噬细胞集落刺激因子(GM-CSF)和白细胞介素4(IL-4)诱导骨髓细胞分化为DC,利用小干涉RNA(siRNA)下调MYSM1的表达,采用免疫荧光微球实验检测BMDC的吞噬功能、流式细胞术检测BMDC的抗原提呈功能、实时定量PCR检测BMDC的IL-6、肿瘤坏死因子α(TNF-α)的mRNA表达变化,探讨MYSM1下调后DC在固有免疫应答中的作用。结果下调MYSM1的表达后,BMDC的吞噬功能无显著变化,抗原提呈功能增强,IL-6、TNF-α的表达增强。结论 MYSM1在固有免疫应答中可以抑制BMDC的抗原提呈功能及炎性细胞因子分泌能力。
引文
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[3]Iwasaki A,Medzhitov R.Control of adaptive immunity by the innate immune system[J].Nat Immunol,2015,16(4):343-353.
[4]Zhu P,Zhou W,Wang J,et al.A histone H2A deubiquitinase complex coordinating histone acetylation and H1 dissociation in transcriptional regulation[J].Mol Cell,2007,27(4):609-621.
[5]Huang X F,Nandakumar V,Tumurkhuu G,et al.Mysm1 is required for interferon regulatory factor expression in maintaining HSC quiescence and thymocyte development[J/OL].Cell Death Dis,2016,7(6):e2260.doi:10.1038/cddis.2016.162.
[6]Wang T,Nandakumar V,Jiang X X,et al.The control of hematopoietic stem cell maintenance,self-renewal,and differentiation by Mysm1-mediated epigenetic regulation[J].Blood,2013,122(16):2812-2822.
[7]Jiang X X,Nguyen Q,Chou Y,et al.Control of B cell development by the histone H2A deubiquitinase MYSM1[J].Immunity,2011,35(6):883-896.
[8]Nandakumar V,Chou Y,Zang L,et al.Epigenetic control of natural killer cell maturation by histone H2A deubiquitinase MYSM1[J].Proc Natl Acad Sci U S A,2013,110(41):E3927-E3936.
[9]Gatzka M,Tasdogan A,Hainzl A,et al.Interplay of H2A deubiquitinase2A-DUB/Mysm1 and the p19(ARF)/p53 axis in hematopoiesis,early T-cell development and tissue differentiation[J].Cell Death Differ,2015,22(9):1451-1462.
[10]Nijnik A,Clare S,Hale C,et al.The critical role of histone H2Adeubiquitinase Mysm1 in hematopoiesis and lymphocyte differentiation[J].Blood,2012,119(6):1370-1379.
[11]Belle J I,Langlais D,Petron J C,et al.p53 mediates loss of hematopoietic stem cell function and lymphopenia in Mysm1 deficiency[J].Blood,2015,125(15):2344-2348.
[12]Zhang Q,Zhao K,Shen Q,et al.Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6[J].Nature,2015,525(7569):389-393.
[13]Meng J,Liu X,Zhang P,et al.Rb selectively inhibits innate IFN-beta production by enhancing deacetylation of IFN-beta promoter through HDAC1 and HDAC8[J].J Autoimmun,2016,73:42-53.
[14]Akira S,Takeda K,Kaisho T.Toll-like receptors:critical proteins linking innate and acquired immunity[J].Nat Immunol,2001,2(8):675-680.
[15]Arnold-Schrauf C,Berod L,Sparwasser T.Dendritic cell specific targeting of My D88 signalling pathways in vivo[J].Eur J Immunol,2015,45(1):32-39.
[16]Liu Q,Ding J L.The molecular mechanisms of TLR-signaling cooperation in cytokine regulation[J].Immunol Cell Biol,2016,94(6):538-542.
[17]Cao X.Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease[J].Nat Rev Immunol,2016,16(1):35-50.
[18]Alvarez-Errico D,Vento-Tormo R,Sieweke M,et al.Epigenetic control of myeloid cell differentiation,identity and function[J].Nat Rev Immunol,2015,15(1):7-17.
[19]Yao Z,Zhang Q,Li X,et al.Death domain-associated protein 6(Daxx)selectively represses IL-6 transcription through histone deacetylase 1(HDAC1)-mediated histone deacetylation in macrophages[J].J Biol Chem,2014,289(13):9372-9379.
[20]Schliehe C,Flynn E K,Vilagos B,et al.The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection[J].Nat Immunol,2015,16(1):67-74.
[21]Liu J,Qian C,Cao X.Post-translational modification control of innate immunity[J].Immunity,2016,45(1):15-30.
[22]Liu Y,Zhang Q,Ding Y,et al.Histone lysine methyltransferase Ezh1 promotes TLR-triggered inflammatory cytokine production by suppressing Tollip[J].J Immunol,2015,194(6):2838-2846.
[23]Jiang X,Chen Z J.The role of ubiquitylation in immune defence and pathogen evasion[J].Nat Rev Immunol,2011,12(1):35-48.
[24]De A,Dainichi T,Rathinam C V,et al.The deubiquitinase activity of A20 is dispensable for NF-kappa B signaling[J].EMBO Rep,2014,15(7):775-783.
[25]Won H,Nandakumar V,Yates P,et al.Epigenetic control of dendritic cell development and fate determination of common myeloid progenitor by Mysm1[J].Blood,2014,124(17):2647-2656.
[26]Panda S,Nilsson J A,Gekara N O.Deubiquitinase MYSM1 regulates innate immunity through inactivation of TRAF3 and TRAF6complexes[J].Immunity,2015,43(4):647-659.