上呼吸道黏膜免疫效应分子λ干扰素的研究进展
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摘要
上呼吸道黏膜与外界环境直接相通,是抵御外来异物入侵的第一道防线,其通过机械性防御屏障及免疫应答的方式防止大量病原体、抗原和外来刺激物等异物的入侵。λ干扰素(IFN-λ)是新近发现的主要产生于黏膜组织的免疫效应分子,其主要是通过激活Janus激酶-信号转导及转录激活因子(JAK-STAT)信号通路发挥生物学效应,JAK-STAT信号通路是将细胞因子刺激信号通过细胞膜进入细胞核内部的重要途径,其参与细胞炎症反应和免疫反应的过程,在调节天然免疫和获得性免疫系统中发挥重要作用,已成为近年来黏膜屏障研究的焦点。
The upper respiratory tract mucosa that can directly communicate with the outside world is the body's first line of defense against the invasion of pathogens,antigens and foreign bodies through mechanical defense barrier and immune response. Interferon-λ( IFN-λ) is a recently discovered immune effector molecule that is mainly produced in mucosa and plays a critical role in the regulation of the innate and adaptive immune systems. IFN-λ has been found to play its biological effects through the activation of Janus kinase-signal transducer and activator of transcription( JAK-STAT) signaling pathway which is one of the major pathways of transmission of cytokine signaling from the cell membrane to the nucleus and widely involved in the inflammatory and immune responses in cells. Recently IFN-λ has been become the focus of mucosal barrier research.
The upper respiratory tract mucosa that can directly communicate with the outside world is the body's first line of defense against the invasion of pathogens,antigens and foreign bodies through mechanical defense barrier and immune response. Interferon-λ( IFN-λ) is a recently discovered immune effector molecule that is mainly produced in mucosa and plays a critical role in the regulation of the innate and adaptive immune systems. IFN-λ has been found to play its biological effects through the activation of Janus kinase-signal transducer and activator of transcription( JAK-STAT) signaling pathway which is one of the major pathways of transmission of cytokine signaling from the cell membrane to the nucleus and widely involved in the inflammatory and immune responses in cells. Recently IFN-λ has been become the focus of mucosal barrier research.
引文
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[24]Jewell NA,Cline T,Mertz SE,et al.Lambda interferon is the predominant interferon induced by influenza A virus infection in vivo[J].J Virol,2010,84(21):11515-11522.
[25]Donnelly RP,Sheikh F,Kotenko SV,et al.The expanded family of classⅡcytokines that share the IL-10 receptor-2(IL-10R2)chain[J].J Leuk Biol,2004,76(2):314-321.
[26]Witte K,Gruetz G,Volk HD,et al.Despite IFN-lambda receptor expression,blood immune cells,but not keratinocytes or melanocytes,have an impaired response to typeⅢinterferons:Implications for therapeutic applications of these cytokines[J].Genes Immun,2009,10(8):702-714.
[27]Langer JA,Cutrone EC,Kotenko S.The ClassⅡcytokine receptor(CRF2)family:Overview and patterns of receptor-ligand interactions[J].Cytokine Growth Factor Rev,2004,15(1):33-48.
[28]Mendoza JL,Schneider WM,Hoffmann HH,et al.The IFN-λ-IFN-λR1-IL-10RβComplex Reveals Structural Features Underlying TypeⅢIFN Functional Plasticity[J].Immunity,2017,46(3):379-392.
[29]Lazear HM,Daniels BP,Pinto AK,et al.Interferon-λrestricts West Nile virus neuroinvasion by tightening the blood-brain barrier[J].Sci Transl Med,2015,7(284):284ra59.
[30]lversen MB,Paludan SR.Mechanisms of typeⅢinterferon expression[J].J Interferon Cytokine Res,2010,30(8):573-578.
[31]Pestka S,Krause CD,Walter MR.Interferons,interferon-like cytokines,and their receptors[J].Immunol Rev,2004,202:8-32.
[32]Dumoutier L,Lejeune D,Hor S,et al.Cloning of a new typeⅡcytokine receptor activating signal transducer and activator of transcription(STAT)1,STAT2 and STAT3[J].Biochem J,2003,370(2):391-396.
[33]Platanias LC.Mechanisms of type-Ⅰ-and type-Ⅱ-interferonmediated signalling[J].Nat Rev Immunol,2005,5(5):375-386.
[34]Ivashkiv LB,Donlin LT.Regulation of typeⅠin terferon responses[J].Nat Rev Immunol,2014,14(1):36-49.
[35]Schneider WM,Chevillotte MD,Rice CM.Interferon-stimulated genes:a complex web of host defenses[J].Annu Rev Immunol,2014,32:513-545.
[36]Zhou Z,Hamming OJ,Ank N,et al.TypeⅢinterferon(IFN)induces a typeⅠIFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases[J].J Virol,2007,81(14):7749-7758.
[37]Andreakos E,Salagianni M,Galani IE,et al.Interferon-λs:FrontLine Guardians of Immunity and Homeostasis in the Respiratory Tract[J].Front Immunol,2017,8:1232.
[38]Galani IE,Koltsida O,Andreakos E.TypeⅢinterferons(IFNs):Emerging Master Regulators of Immunity[J].Adv Exp Med Biol,2015,850:1-15.
[39]Wack A,Terczyńska-Dyla E,Hartmann R.Guarding the frontiers:The biology of typeⅢinterferons[J].Nat Immunol,2015,16(8):802-809.
[40]Klinkhammer J,Schnepf D,Ye L,et al.IFN-λprevents influenza virus spread from the upper airways to the lungs and limits virus transmission[J].Elife,2018,7.pii:e33354.
[41]Kim S,Kim MJ,Kim CH,et al.The Superiority of IFN-λas a Therapeutic Candidate to Control Acute Influenza Viral Lung Infection[J].Am J Respir Cell Mol Biol,2017,56(2):202-212.
[42]Sun Y,Jiang J,Tien P,et al.IFN-λ:A new spotlight in innate immunity against influenza virus infection[J].Protein Cell,2018,9(10):832-837.
[43]Ank N,West H,Bartholdy C,et al.Lambda interferon(IFN-lambda),a typeⅢIFN,is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo[J].J Virol,2006,80(9):4501-4509.
[44]Vachon VK,Calderon BM,Conn GL.A novel RNA molecular signature for activation of 2'-5'oligoadenylate synthetase-1[J].Nucleic Acids Res,2014,43(1):544-552.
[45]Silverman RH.Viral encounters with 2',5'-oligoadenylate synthetase and RNase L during the interferon antiviral response[J].J Virol,2007,81(23):12720-12729.
[46]Liu D,Mao HL,Gu MH,et al.The transcription regulation analysis of Ctenopharyngodon idellus PKR and PKZ genes[J].Gene,2016,576:512-519.
[47]Rabouw HH,Langereis MA,Knaap RC,et al.Middle East Respiratory Coronavirus Accessory Protein 4a Inhibits PKR-Mediated Antiviral Stress Responses[J].PLo S Pathog,2016,12(10):e1005982.
[48]Wells AI,Coyne CB.TypeⅢInterferons in Antiviral Defenses at Barrier Surface[J].Trends Immunol,2018,39(10):848-858.
[49]Andreakos E,Zanoni I,Galani IE.Lambda interferons come to light:Dual function cytokines mediating antiviral immunity and damage control[J].Curr Opin Immunol,2018,56:67-75.
[50]Odendall C,Voak AA,Kagan JC.TypeⅢIFNs Are Commonly Induced by Bacteria-Sensing TLRs and Reinforce Epithelial Barriers during Infection[J].J Immunol,2017,199(9):3270-3279.
[51]Mennechet FJ,Uze G.Interferon-lambda-treated dendritic cells specifically induce proliferation of FOXP3-expressing suppressor T cells[J].Blood,2006,107(11):4417-4423.
[52]Zanoni l,Granucci F,Broggi A.Interferon(IFN)-λTakes the Helm:Immunomodulatory Roles of TypeⅢIFNs[J].Front Immunol,2017,8:1661.
[53]Finotti G,Tamassia N,Cassatella MA.Synergistic production of TNFαand IFNαby human p DCs incubated with IFNλ3 and IL-3[J].Cytokine,2016,86:124-131.
[54]Jordan WJ,Eskdale J,Boniotto M,et al.Modulation of the human cytokine response by interferon lambda-1(IFN-λ1/IL-29)[J].Genes Immun,2007,8(1):13-20.
[2]Kotenko SV,Gallagher G,Baurin VV,et al.IFN-lambdas mediate antiviral protection through a distinct classⅡcytokine receptor complex[J].Nat Immunol,2003,4(1):69-77.
[3]Prokunina-Olsson L,Muchmore B,Tang W,et al.A variant upstream of IFNL3(IL28B)creating a new interferon gene IFNL4is associated with impaired clearance of hepatitis C virus[J].Nat Genet,2013,45(2):164-171.
[4]Hamming OJ,Terczyńska-Dyla E,Vieyres G,et al.Interferon lambda 4 signals via the IFNλreceptor to regulate antiviral activity against HCV and coronaviruses[J].EMBO J,2013,32(23):3055-3065.
[5]Lasfar A,Lewis-Antes A,Smirnov SV,et al.Characterization of the mouse IFN-lambda ligand-receptor system:IFN-lambdas exhibit antitumor activity against B16 melanoma[J].Cancer Res,2006,66(8):4468-4477.
[6]Dixit E,Boulant S,Zhang Y,et al.Peroxisomes are signaling platforms for antiviral innate immunity[J].Cell,2010,141(4):668-681.
[7]Odendall C,Dixit E,Stavru F,et al.Diverse intracellular pathogens activate typeⅢinterferon expression from peroxisomes[J].Nat Immunol,2014,15(8):717-726.
[8]Lazear HM,Nice TJ,Diamond MS.Interferon-lambda:Immune Functions at Barrier Surfaces and Beyond[J].Immunity,2015,43(1):15-28.
[9]Osterlund PI,Pietila TE,Veckman V,et al.IFN regulatory factor family members differentially regulate the expression of typeⅢIFN(IFN-λ)genes[J].J Immunol,2007,179(60):3434-3442.
[10]Langhans B,Kupfer B,Braunschweiger L,et al.Interferon-lambda serum levels in hepatitis C[J].J Hepatol,2011,54(5):859-865.
[11]Sommereyns C,Paul S,Staeheli P,et al.IFN-lambda(IFN-lambda)is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo[J].PLo S Pathog,2008,4(3):e1000017.
[12]Mordstein M,Kochs G,Dumoutier L,et al.Interferon-λContributes to Innate Immunity of Mice against Influenza A Virus but Not against Hepatotropic Viruses[J].PLo S Pathog,2008,4(9):e1000151.
[13]Mordstein M,Neugebauer E,Ditt V,et al.Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections[J].J Virol,2010,84(11):5670-5677.
[14]Pulverer JE,Rand U,Lienenklaus S,et al.Temporal and Spatial Resolution of TypeⅠandⅢInterferon Responses In Vivo[J].J Virol,2010,84(17):8626-8638.
[15]Lasfar A,Abushahba W,Balan M,et al.Interferon lambda:Anew sword in cancer immunotherapy[J].Clin Dev Immunol,2011,2011:349575.
[16]Coccia EM,Severa M,Giacomini E,et al.Viral infection and Tolllike receptor agonists induce a differential expression of typeⅠand lambda interferons in human plasmacytoid and monocytederived dendritic cells[J].Eur J Immunol,2004,34(3):796-805.
[17]Spann KM,Tran KC,Chi B,et al.Suppression of the induction of alpha,beta,and lambda interferons by the NS1 and NS2 proteins of human respiratory syncytial virus in human epithelial cells and macrophages[J].J Virol,2004,78(8):4363-4369.
[18]Ank N,Iversen MB,Bartholdy C,et al.An important role for typeⅢinterferon(IFN-lambda/IL-28)in TLR-induced antiviral activity[J].J Immunol,2008,180(4):2474-2485.
[19]Okabayashi T,Kojima T,Masaki T,et al.Type-Ⅲinterferon,not type-Ⅰ,is the predominant interferon induced by respiratory viruses in nasal epithelial cells[J].Virus Res,2011,160(1/2):360-366.
[20]Kim HJ,Kim CH,Ryu JH,et al.Reactive Oxygen Species Induce Antiviral Innate Immune Response through IFN-λRegulation in Human Nasal Epithelial Cells[J].Am J Respir Cell Mol Biol,2013,49(5):855-865.
[21]Galani IE,Triantafyllia V,Eleminiadou EE,et al.Interferon-λMediates Non-redundant Front-Line Antiviral Protection against Influenza Virus Infection without Compromising Host Fitness[J].Immunity,2017,46(5):875-890.
[22]Crotta S,Davidson S,Mahlakoiv T,et al.TypeⅠand typeⅢinterferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia[J].PLo S Pathog,2013,9(11):e1003773.
[23]Fox JM,Crabtree JM,Sage LK,et al.Interferon Lambda Upregulates IDO1 Expression in Respiratory Epithelial Cells After Influenza Virus Infection[J].J Interferon Cytokine Res,2015,35(7):554-562.
[24]Jewell NA,Cline T,Mertz SE,et al.Lambda interferon is the predominant interferon induced by influenza A virus infection in vivo[J].J Virol,2010,84(21):11515-11522.
[25]Donnelly RP,Sheikh F,Kotenko SV,et al.The expanded family of classⅡcytokines that share the IL-10 receptor-2(IL-10R2)chain[J].J Leuk Biol,2004,76(2):314-321.
[26]Witte K,Gruetz G,Volk HD,et al.Despite IFN-lambda receptor expression,blood immune cells,but not keratinocytes or melanocytes,have an impaired response to typeⅢinterferons:Implications for therapeutic applications of these cytokines[J].Genes Immun,2009,10(8):702-714.
[27]Langer JA,Cutrone EC,Kotenko S.The ClassⅡcytokine receptor(CRF2)family:Overview and patterns of receptor-ligand interactions[J].Cytokine Growth Factor Rev,2004,15(1):33-48.
[28]Mendoza JL,Schneider WM,Hoffmann HH,et al.The IFN-λ-IFN-λR1-IL-10RβComplex Reveals Structural Features Underlying TypeⅢIFN Functional Plasticity[J].Immunity,2017,46(3):379-392.
[29]Lazear HM,Daniels BP,Pinto AK,et al.Interferon-λrestricts West Nile virus neuroinvasion by tightening the blood-brain barrier[J].Sci Transl Med,2015,7(284):284ra59.
[30]lversen MB,Paludan SR.Mechanisms of typeⅢinterferon expression[J].J Interferon Cytokine Res,2010,30(8):573-578.
[31]Pestka S,Krause CD,Walter MR.Interferons,interferon-like cytokines,and their receptors[J].Immunol Rev,2004,202:8-32.
[32]Dumoutier L,Lejeune D,Hor S,et al.Cloning of a new typeⅡcytokine receptor activating signal transducer and activator of transcription(STAT)1,STAT2 and STAT3[J].Biochem J,2003,370(2):391-396.
[33]Platanias LC.Mechanisms of type-Ⅰ-and type-Ⅱ-interferonmediated signalling[J].Nat Rev Immunol,2005,5(5):375-386.
[34]Ivashkiv LB,Donlin LT.Regulation of typeⅠin terferon responses[J].Nat Rev Immunol,2014,14(1):36-49.
[35]Schneider WM,Chevillotte MD,Rice CM.Interferon-stimulated genes:a complex web of host defenses[J].Annu Rev Immunol,2014,32:513-545.
[36]Zhou Z,Hamming OJ,Ank N,et al.TypeⅢinterferon(IFN)induces a typeⅠIFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases[J].J Virol,2007,81(14):7749-7758.
[37]Andreakos E,Salagianni M,Galani IE,et al.Interferon-λs:FrontLine Guardians of Immunity and Homeostasis in the Respiratory Tract[J].Front Immunol,2017,8:1232.
[38]Galani IE,Koltsida O,Andreakos E.TypeⅢinterferons(IFNs):Emerging Master Regulators of Immunity[J].Adv Exp Med Biol,2015,850:1-15.
[39]Wack A,Terczyńska-Dyla E,Hartmann R.Guarding the frontiers:The biology of typeⅢinterferons[J].Nat Immunol,2015,16(8):802-809.
[40]Klinkhammer J,Schnepf D,Ye L,et al.IFN-λprevents influenza virus spread from the upper airways to the lungs and limits virus transmission[J].Elife,2018,7.pii:e33354.
[41]Kim S,Kim MJ,Kim CH,et al.The Superiority of IFN-λas a Therapeutic Candidate to Control Acute Influenza Viral Lung Infection[J].Am J Respir Cell Mol Biol,2017,56(2):202-212.
[42]Sun Y,Jiang J,Tien P,et al.IFN-λ:A new spotlight in innate immunity against influenza virus infection[J].Protein Cell,2018,9(10):832-837.
[43]Ank N,West H,Bartholdy C,et al.Lambda interferon(IFN-lambda),a typeⅢIFN,is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo[J].J Virol,2006,80(9):4501-4509.
[44]Vachon VK,Calderon BM,Conn GL.A novel RNA molecular signature for activation of 2'-5'oligoadenylate synthetase-1[J].Nucleic Acids Res,2014,43(1):544-552.
[45]Silverman RH.Viral encounters with 2',5'-oligoadenylate synthetase and RNase L during the interferon antiviral response[J].J Virol,2007,81(23):12720-12729.
[46]Liu D,Mao HL,Gu MH,et al.The transcription regulation analysis of Ctenopharyngodon idellus PKR and PKZ genes[J].Gene,2016,576:512-519.
[47]Rabouw HH,Langereis MA,Knaap RC,et al.Middle East Respiratory Coronavirus Accessory Protein 4a Inhibits PKR-Mediated Antiviral Stress Responses[J].PLo S Pathog,2016,12(10):e1005982.
[48]Wells AI,Coyne CB.TypeⅢInterferons in Antiviral Defenses at Barrier Surface[J].Trends Immunol,2018,39(10):848-858.
[49]Andreakos E,Zanoni I,Galani IE.Lambda interferons come to light:Dual function cytokines mediating antiviral immunity and damage control[J].Curr Opin Immunol,2018,56:67-75.
[50]Odendall C,Voak AA,Kagan JC.TypeⅢIFNs Are Commonly Induced by Bacteria-Sensing TLRs and Reinforce Epithelial Barriers during Infection[J].J Immunol,2017,199(9):3270-3279.
[51]Mennechet FJ,Uze G.Interferon-lambda-treated dendritic cells specifically induce proliferation of FOXP3-expressing suppressor T cells[J].Blood,2006,107(11):4417-4423.
[52]Zanoni l,Granucci F,Broggi A.Interferon(IFN)-λTakes the Helm:Immunomodulatory Roles of TypeⅢIFNs[J].Front Immunol,2017,8:1661.
[53]Finotti G,Tamassia N,Cassatella MA.Synergistic production of TNFαand IFNαby human p DCs incubated with IFNλ3 and IL-3[J].Cytokine,2016,86:124-131.
[54]Jordan WJ,Eskdale J,Boniotto M,et al.Modulation of the human cytokine response by interferon lambda-1(IFN-λ1/IL-29)[J].Genes Immun,2007,8(1):13-20.