干扰素刺激基因及临床意义研究进展
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摘要
干扰素(Interferon,IFN)作用于靶细胞表面受体后,通过一系列信号传导激活干扰素刺激基因(Interferon stimulated genes,ISGs)的表达。干扰素刺激基因及其表达产物具有抗病毒、免疫调控等多种生物学功能,是干扰素发挥功能的重要效应分子,同时具有潜在的临床意义。众多国内外研究发现ISGs对Ⅰ型干扰素临床抗病毒效果具有预测意义,同时可能成为某些自身免疫疾病临床诊断的新靶标以及作为一些肿瘤治疗药物新靶点等潜在应用价值。本文将从干扰素刺激基因的诱导产生、抗病毒等生物学功能以及潜在临床意义方面展开综述。
Interferon(IFN) acts on the surface of the target cell receptors and activate the expression of interferon stimulated genes( interferon stimulated genes,ISGs) through a series of signal transduction. ISGs have antiviral and immunomodulation and other biological functions,indicating ISGs are important molecules for interferon to function and have some potential clinical significance. A large number of research results showed that ISGs may predict the antiviral effect of IFN-α;specific expression of ISGs in patients with autoimmune diseases in vivo may be used as a new biomarker for clinical diagnosis of the diseases;ISGs may act as a new target for cancer treatment and have other potential applications. This review mainly focuses on the induction,the biological functions like antiviral effects and the potential clinical significance of ISGs.
Interferon(IFN) acts on the surface of the target cell receptors and activate the expression of interferon stimulated genes( interferon stimulated genes,ISGs) through a series of signal transduction. ISGs have antiviral and immunomodulation and other biological functions,indicating ISGs are important molecules for interferon to function and have some potential clinical significance. A large number of research results showed that ISGs may predict the antiviral effect of IFN-α;specific expression of ISGs in patients with autoimmune diseases in vivo may be used as a new biomarker for clinical diagnosis of the diseases;ISGs may act as a new target for cancer treatment and have other potential applications. This review mainly focuses on the induction,the biological functions like antiviral effects and the potential clinical significance of ISGs.
引文
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[2]Sj9strand,Maria.The role of interferon-regulated genes in the immune system.[J/OL].Solna:Karolinska Institutet,2017.https://openarchive.ki.se/xmlui/handle/10616/45465.
[3]Hoffmann HH,Schneider WM,Rice CM.Interferons and viruses:an evolutionary arms race of molecular interactions[J].Trends Immunol,2015,36(3):124.
[4]Stark GR,Jr DJ.The JAK-STAT pathway at twenty[J].Immunity,2012,36(4):503-514.
[5]Schneider WM,Chevillotte MD,Rice CM.Interferon-stimulated genes:a complex web of host defenses[J].Annual Rev Immunol,2014,32(1):513-545.
[6]Oon S,Wilson NJ,Wicks I.Targeted therapeutics in SLE:emerging strategies to modulate the interferon pathway[J].Clin Trans Immunol,2016,5(5):e79.
[7]Sen GC,Peters GA.Viral stress-inducible genes[J].Adv Virus Res,2007,70(70):233-263.
[8]Haller O,Staeheli P,Schwemmle M,et al.Mx GTPases:dynaminlike antiviral machines of innate immunity[J].Trends Microbiol,2015,23(3):154.
[9]Goujon C.MX2 and HIV-1 Restriction[M].New York:Springer,2015:1-8.
[10]Anggakusuma,Romerobrey I,Berger C,et al.Interferon-inducible cholesterol-25-hydroxylase restricts hepatitis C virus replication through blockage of membranous web formation[J].Hepatology,2015,62(3):702-714.
[11]Savidis G,Perreira JM,Portmann JM,et al.The IFITMs Inhibit Zika Virus Replication[J].Cell Rep,2016,15(11):2323.
[12]Stremlau M,Owens CM,Perron MJ,et al.The cytoplasmic body component TRIM5[alpha]restricts HIV-1 infection in Old World monkeys[J].Nature,2004,427(6977):848-853.
[13]Barr SD,Smiley JR,Bushman FD.The Interferon response inhibits HIV particle production by induction of TRIM22[J].PLo S Patho,2008,4(2):e1000007.
[14]Silverman RH.Viral encounters with 2',5'-oligoadenylate synthetase and RNase L during the interferon antiviral response[J].JVirol,2007,81(23):12720-12729.
[15]Ibsen MS,Gad HH,Andersen LL,et al.Structural and functional analysis reveals that human OASL binds dsRNA to enhance RIG-Isignaling[J].Nucleic Acids Res,2015,43(10):5236.
[16]王爱华,管世鹤,杨凯,等.干扰素诱导的双链RNA依赖性蛋白激酶体外抗乙型肝炎病毒活性的研究[J].中国药理学通报,2015,31(9):1254-1258.Wang AH,Guan SH,Yang K,et al.Study of IFN-inducible double-stranded RNA dependent protein kinase on antiviral activity of HBV in vitro[J].Chin Pharmacological Bullet,2015,31(9):1254-1258.
[17]Bianco C,Mohr I.Restriction of HCMV replication by ISG15,a host effector regulated by c GAS-STING ds DNA sensing[J].J Virol,2017,91(9):e0483.
[18]Nasr N,Maddocks S,Turville SG,et al.HIV-1 infection of human macrophages directly induces viperin which inhibits viral production[J].Blood,2012,120(4):778-788.
[19]朱春辉,汤艳东,徐方,等.抗病毒免疫因子Viperin的研究进展[J].病毒学报,2015,13(1):91-96.Zhu CH,Tang YD,Xu F,et al.Progress in studies of Viperin,an important cellular antiviral factor[J].Chin J Virol,2015,13(1):91-96.
[20]Liu Y,Luo S,He S,et al.Tetherin restricts HSV-2 release and is counteracted by multiple viral glycoproteins[J].Virology,2015,475:96-109.
[21]Piganis RA.Suppressor of cytokine signaling(SOCS)1 inhibits type I interferon(IFN)signaling via the interferon alpha receptor(IFNAR1)-associated tyrosine kinase Tyk2[J].Biol Chem,2011,28(39):33811-33818.
[22]Basters A,Geurink PP,Oualid FE,et al.Molecular characterization of ubiquitin-specific protease 18 reveals substrate specificity for interferon-stimulated gene 15[J].Febs J,2014,281(7):1918-1928.
[23]Macparland SA,Ma XZ,Chen L,et al.Lipopolysaccharide and tumor necrosis factor alpha inhibit interferon signaling in hepatocytes by increasing ubiquitin-like protease 18(USP18)expression[J].J Virol,2016,90(12):5549-5560.
[24]Ning Li,Lei Zhang,Chen L,et al.Mx A inhibits hepatitis B virus replication by interaction with hepatitis B core antigen[J].Hepatology,2012,56(3):803-811.
[25]Park IH,Kwon YC,Ryu WS,et al.Inhibition of hepatitis B virus replication by ligand-mediated activation of RNase L[J].Antiviral Res,2014,104(1):118-127.
[26]Kim KI,Kim SR,Sasase N,et al.2'-,5'-Oligoadenylate synthetase response ratio predicting virological response to PEG-interferonalpha2b plus ribavirin therapy in patients with chronic hepatitis C[J].J Clin Pharm Therap,2006,31(5):441-446.
[27]Shindo M,Hamada K,Morikawa T,et al.In vivo interferon system assessed by 2'-5'oligoadenylate synthetase activity in chronic hepatitis C virus patients treated with pegylated interferon and ribavirin[J].Hepatol Res Official J Japan Soc Hepatol,2008,38(12):1213-1220.
[28]Xiao C,Qin B,Chen L,et al.Preactivation of the interferon signalling in liver is correlated with nonresponse to interferon alpha therapy in patients chronically infected with hepatitis B virus[J].J Viral Hepatitis,2012,19(2):e1-e10.
[29]Chen L,Borozan I,Feld J,et al.Hepatic gene expression discri minates responders and nonresponders in treatment of chronic hepatitis C viral infection[J].Gastroenterology,2005,128(5):1437-1444.
[30]Li L,Lei QS,Zhang SJ,et al.Suppression of USP18 potentiates the anti-HBV activity of interferon alpha in Hep G2.2.15 cells via JAK/STAT signaling[J].PLo S One,2016,11(5):e0156496.
[31]Li Y,Li S,Duan X,et al.Interferon-stimulated gene 15conjugation stimulates hepatitis B virus production independent of type I interferon signaling pathway in vitro[J].Mediators Inflamm,2016,2016(6):7417648.
[32]Shereen O,Wilson NJ,Ian W.Targeted therapeutics in SLE:emerging strategies to modulate the interferon pathway:[J].Clin Trans Immunol,2016,5(5):e79.
[33]Grammatikos AP,Kyttaris VC,Kis-Toth K,et al.A T cell gene expression panel for the diagnosis and monitoring of disease activity in patients with systemic lupus erythematosus[J].Clin Immunol,2014,150(2):192-200.
[34]Yuan Y,Ma H,Ye Z,et al.Interferon-stimulated gene 15expression in systemic lupus erythematosus:Diagnostic value and association with lymphocytopenia[J]Z Rheumatol,2017.doi:10.1007/s00393-017-0274-8.
[35]Salajeheh M,Kong SW,Pinkus JL,et al.Interferon-stimulated gene 15(ISG15)conjugates proteins in dermatomyositis muscle with perifascicular atrophy[J].Ann Neurol,2010,67(1):53-63.
[36]Malhotra S,Morcillo-Suarcz C,Nurtdinov R,et al.Roles of the ubiquitin peptidase USP18 in multiple sclerosis and the response to interferon-βtreatment[J].Eur J Neurol,2013,20(10):1390-1397.
[37]Chang X,Yue L,Liu W,et al.CD38 and E2F transcription factor2 have uniquely increased expression in rheumatoid arthritis synovial tissues[J].Clin Exp Immunol,2014,176(2):222-231.
[38]Baarsen LGMV,Vosslamber S,Tijssen M,et al.Pharmacogenomics of interferon-therapy in multiple sclerosis:baseline IFN signature determines pharmacological differences between patients[J].PLo S One,2008,3(4):e1927.
[39]Fridman WH,Pages F,Sautes-Fridman C,et al.The immune contexture in human tumours:impact on clinical outcome[J].Nat Rev Cancer,2012,12(4):298-306.
[40]Stiff A,Carson IW.Investigations of interferon-lambda for the treatment of cancer[J].J Innate Immunity,2015,7(3):243-250.
[41]Guo Y,Dolinko AV,Chinyengetere F,et al.Blockade of the ubiquitin protease UBP43 destabilizes transcription factor PML/RARalpha and inhibits the gowth of acute promyelocytic leukemia[J].Cancer Res,2010,70(23):9875-9885.
[42]Guo Y,Chinyengetere F,Dolinko AV,et al.Evidence for the ubiquitin protease UBP43 as an antineoplastic target[J].Mole Cancer Therapeutics,2012,11(9):1968-1977.
[43]Burkart C,Arimoto K,Tang T,et al.Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN-λand elevated secretion of Cxcl10[J].Embo Mole Med,2013,5(7):1035-1050.
[44]Duex JE,Comeau L,Sorkin A,et al.Usp18 regulates epidermal growth factor(EGF)receptor expression and cancer cell survival via MicroRNA-7[J].J Biol Chem,2011,286(28):25377-25386.
[45]Xiang Y,Wang Z,Murakami J,et al.Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2',5'-oligoadenylates[J].Cancer Res,2003,63(20):6795-6801.
[46]Maia CJ,Rocha SM,Socorro S,et al.Oligoadenylate synthetase 1(OAS1)expression in human breast and prostate cancer cases,and its regulation by sex steroid hormones[J].Adv Modern Oncol Res,2016,2(2):97-104.
[2]Sj9strand,Maria.The role of interferon-regulated genes in the immune system.[J/OL].Solna:Karolinska Institutet,2017.https://openarchive.ki.se/xmlui/handle/10616/45465.
[3]Hoffmann HH,Schneider WM,Rice CM.Interferons and viruses:an evolutionary arms race of molecular interactions[J].Trends Immunol,2015,36(3):124.
[4]Stark GR,Jr DJ.The JAK-STAT pathway at twenty[J].Immunity,2012,36(4):503-514.
[5]Schneider WM,Chevillotte MD,Rice CM.Interferon-stimulated genes:a complex web of host defenses[J].Annual Rev Immunol,2014,32(1):513-545.
[6]Oon S,Wilson NJ,Wicks I.Targeted therapeutics in SLE:emerging strategies to modulate the interferon pathway[J].Clin Trans Immunol,2016,5(5):e79.
[7]Sen GC,Peters GA.Viral stress-inducible genes[J].Adv Virus Res,2007,70(70):233-263.
[8]Haller O,Staeheli P,Schwemmle M,et al.Mx GTPases:dynaminlike antiviral machines of innate immunity[J].Trends Microbiol,2015,23(3):154.
[9]Goujon C.MX2 and HIV-1 Restriction[M].New York:Springer,2015:1-8.
[10]Anggakusuma,Romerobrey I,Berger C,et al.Interferon-inducible cholesterol-25-hydroxylase restricts hepatitis C virus replication through blockage of membranous web formation[J].Hepatology,2015,62(3):702-714.
[11]Savidis G,Perreira JM,Portmann JM,et al.The IFITMs Inhibit Zika Virus Replication[J].Cell Rep,2016,15(11):2323.
[12]Stremlau M,Owens CM,Perron MJ,et al.The cytoplasmic body component TRIM5[alpha]restricts HIV-1 infection in Old World monkeys[J].Nature,2004,427(6977):848-853.
[13]Barr SD,Smiley JR,Bushman FD.The Interferon response inhibits HIV particle production by induction of TRIM22[J].PLo S Patho,2008,4(2):e1000007.
[14]Silverman RH.Viral encounters with 2',5'-oligoadenylate synthetase and RNase L during the interferon antiviral response[J].JVirol,2007,81(23):12720-12729.
[15]Ibsen MS,Gad HH,Andersen LL,et al.Structural and functional analysis reveals that human OASL binds dsRNA to enhance RIG-Isignaling[J].Nucleic Acids Res,2015,43(10):5236.
[16]王爱华,管世鹤,杨凯,等.干扰素诱导的双链RNA依赖性蛋白激酶体外抗乙型肝炎病毒活性的研究[J].中国药理学通报,2015,31(9):1254-1258.Wang AH,Guan SH,Yang K,et al.Study of IFN-inducible double-stranded RNA dependent protein kinase on antiviral activity of HBV in vitro[J].Chin Pharmacological Bullet,2015,31(9):1254-1258.
[17]Bianco C,Mohr I.Restriction of HCMV replication by ISG15,a host effector regulated by c GAS-STING ds DNA sensing[J].J Virol,2017,91(9):e0483.
[18]Nasr N,Maddocks S,Turville SG,et al.HIV-1 infection of human macrophages directly induces viperin which inhibits viral production[J].Blood,2012,120(4):778-788.
[19]朱春辉,汤艳东,徐方,等.抗病毒免疫因子Viperin的研究进展[J].病毒学报,2015,13(1):91-96.Zhu CH,Tang YD,Xu F,et al.Progress in studies of Viperin,an important cellular antiviral factor[J].Chin J Virol,2015,13(1):91-96.
[20]Liu Y,Luo S,He S,et al.Tetherin restricts HSV-2 release and is counteracted by multiple viral glycoproteins[J].Virology,2015,475:96-109.
[21]Piganis RA.Suppressor of cytokine signaling(SOCS)1 inhibits type I interferon(IFN)signaling via the interferon alpha receptor(IFNAR1)-associated tyrosine kinase Tyk2[J].Biol Chem,2011,28(39):33811-33818.
[22]Basters A,Geurink PP,Oualid FE,et al.Molecular characterization of ubiquitin-specific protease 18 reveals substrate specificity for interferon-stimulated gene 15[J].Febs J,2014,281(7):1918-1928.
[23]Macparland SA,Ma XZ,Chen L,et al.Lipopolysaccharide and tumor necrosis factor alpha inhibit interferon signaling in hepatocytes by increasing ubiquitin-like protease 18(USP18)expression[J].J Virol,2016,90(12):5549-5560.
[24]Ning Li,Lei Zhang,Chen L,et al.Mx A inhibits hepatitis B virus replication by interaction with hepatitis B core antigen[J].Hepatology,2012,56(3):803-811.
[25]Park IH,Kwon YC,Ryu WS,et al.Inhibition of hepatitis B virus replication by ligand-mediated activation of RNase L[J].Antiviral Res,2014,104(1):118-127.
[26]Kim KI,Kim SR,Sasase N,et al.2'-,5'-Oligoadenylate synthetase response ratio predicting virological response to PEG-interferonalpha2b plus ribavirin therapy in patients with chronic hepatitis C[J].J Clin Pharm Therap,2006,31(5):441-446.
[27]Shindo M,Hamada K,Morikawa T,et al.In vivo interferon system assessed by 2'-5'oligoadenylate synthetase activity in chronic hepatitis C virus patients treated with pegylated interferon and ribavirin[J].Hepatol Res Official J Japan Soc Hepatol,2008,38(12):1213-1220.
[28]Xiao C,Qin B,Chen L,et al.Preactivation of the interferon signalling in liver is correlated with nonresponse to interferon alpha therapy in patients chronically infected with hepatitis B virus[J].J Viral Hepatitis,2012,19(2):e1-e10.
[29]Chen L,Borozan I,Feld J,et al.Hepatic gene expression discri minates responders and nonresponders in treatment of chronic hepatitis C viral infection[J].Gastroenterology,2005,128(5):1437-1444.
[30]Li L,Lei QS,Zhang SJ,et al.Suppression of USP18 potentiates the anti-HBV activity of interferon alpha in Hep G2.2.15 cells via JAK/STAT signaling[J].PLo S One,2016,11(5):e0156496.
[31]Li Y,Li S,Duan X,et al.Interferon-stimulated gene 15conjugation stimulates hepatitis B virus production independent of type I interferon signaling pathway in vitro[J].Mediators Inflamm,2016,2016(6):7417648.
[32]Shereen O,Wilson NJ,Ian W.Targeted therapeutics in SLE:emerging strategies to modulate the interferon pathway:[J].Clin Trans Immunol,2016,5(5):e79.
[33]Grammatikos AP,Kyttaris VC,Kis-Toth K,et al.A T cell gene expression panel for the diagnosis and monitoring of disease activity in patients with systemic lupus erythematosus[J].Clin Immunol,2014,150(2):192-200.
[34]Yuan Y,Ma H,Ye Z,et al.Interferon-stimulated gene 15expression in systemic lupus erythematosus:Diagnostic value and association with lymphocytopenia[J]Z Rheumatol,2017.doi:10.1007/s00393-017-0274-8.
[35]Salajeheh M,Kong SW,Pinkus JL,et al.Interferon-stimulated gene 15(ISG15)conjugates proteins in dermatomyositis muscle with perifascicular atrophy[J].Ann Neurol,2010,67(1):53-63.
[36]Malhotra S,Morcillo-Suarcz C,Nurtdinov R,et al.Roles of the ubiquitin peptidase USP18 in multiple sclerosis and the response to interferon-βtreatment[J].Eur J Neurol,2013,20(10):1390-1397.
[37]Chang X,Yue L,Liu W,et al.CD38 and E2F transcription factor2 have uniquely increased expression in rheumatoid arthritis synovial tissues[J].Clin Exp Immunol,2014,176(2):222-231.
[38]Baarsen LGMV,Vosslamber S,Tijssen M,et al.Pharmacogenomics of interferon-therapy in multiple sclerosis:baseline IFN signature determines pharmacological differences between patients[J].PLo S One,2008,3(4):e1927.
[39]Fridman WH,Pages F,Sautes-Fridman C,et al.The immune contexture in human tumours:impact on clinical outcome[J].Nat Rev Cancer,2012,12(4):298-306.
[40]Stiff A,Carson IW.Investigations of interferon-lambda for the treatment of cancer[J].J Innate Immunity,2015,7(3):243-250.
[41]Guo Y,Dolinko AV,Chinyengetere F,et al.Blockade of the ubiquitin protease UBP43 destabilizes transcription factor PML/RARalpha and inhibits the gowth of acute promyelocytic leukemia[J].Cancer Res,2010,70(23):9875-9885.
[42]Guo Y,Chinyengetere F,Dolinko AV,et al.Evidence for the ubiquitin protease UBP43 as an antineoplastic target[J].Mole Cancer Therapeutics,2012,11(9):1968-1977.
[43]Burkart C,Arimoto K,Tang T,et al.Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN-λand elevated secretion of Cxcl10[J].Embo Mole Med,2013,5(7):1035-1050.
[44]Duex JE,Comeau L,Sorkin A,et al.Usp18 regulates epidermal growth factor(EGF)receptor expression and cancer cell survival via MicroRNA-7[J].J Biol Chem,2011,286(28):25377-25386.
[45]Xiang Y,Wang Z,Murakami J,et al.Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2',5'-oligoadenylates[J].Cancer Res,2003,63(20):6795-6801.
[46]Maia CJ,Rocha SM,Socorro S,et al.Oligoadenylate synthetase 1(OAS1)expression in human breast and prostate cancer cases,and its regulation by sex steroid hormones[J].Adv Modern Oncol Res,2016,2(2):97-104.