IFN-Is at the interface of Innate and Adapative Immunity
IFN-Is at the interface of Innate and Adapative Immunity
批准号:
7916939
负责人:
CHRISTIAN W SCHINDLER
金额:
$23.51万
依托单位国家:
美国
项目类别:
财政年份:
2009
资助国家:
美国
项目状态:
已结题
起止时间:
2009-09-15 至 2010-03-31
关键词:
AccountingAntigen-Presenting CellsAntiviral AgentsAreaBindingBiochemicalBiologicalCell NucleusCellsComplexCytokine Inducible SH2-Containing ProteinDendritic CellsExhibitsFamilyFibroblastsGene ExpressionGene TargetingGenesGeneticHistocompatibility Antigens Class IIHumanIFNAR1 geneImmuneImmune responseImmunityInterferon Type IInterferon Type IIInterferon-alphaInterferon-betaInterferonsInvestigationKineticsKnockout MiceMHC Class II GenesMediatingModificationMusNuclear ImportPathogenesisPathway interactionsPhosphoric Monoester HydrolasesPlayPrincipal InvestigatorPropertyProteinsRecruitment ActivityRegulationRoleSignal PathwaySignal TransductionSystemic Lupus ErythematosusTissuesTyrosine PhosphorylationUbiquitinUp-RegulationVirusVirus Diseasescytokinein vitro activitymacrophagemanprogramsprotein inhibitors of activated STATreceptorresponsetranscription factortype I interferon receptorubiquitin-protein ligase
中文摘要
描述(由申请人提供):干扰素(IFN),最初被鉴定为其有效的抗病毒活性,可分为两大类。其中,II型或免疫性干扰素(又名干扰素-γ)已经赢得了很多恶名,但I型干扰素(干扰素-是;例如,干扰素-α,干扰素-β等)代表着一个更大更复杂的家庭。与此一致的是,病毒已经进化出许多策略来抑制干扰素-I的活性。最近,干扰素-IS也获得了一些知名度,人们认识到它们是由浆vtoid树突状细胞(PDCs,又名)分泌的主要效应细胞因子。“天然产生干扰素-I的细胞”)。然后这些干扰素调节先天免疫和获得性免疫的各个方面。也有有趣的新证据表明,干扰素-IS和pDC在系统性红斑狼疮(SLE)的发病机制中发挥着重要作用。
像其他细胞因子一样,干扰素-1通过诱导新的基因来诱导它们的有效活性。对干扰素-α快速诱导基因的能力的表征导致了前两个STAT转录因子STAT1和STAT2的发现。这些STATs通过未知的机制被招募到I型干扰素受体(IFNAR),然后它们被激活(通过酪氨酸磷酸化),二聚体,移位到细胞核并激活基因。相反,干扰素-伽马只通过STAT1传递其信号,尽管动力学不同。
为了确定Stat2在干扰素-IS的生物学反应中所起的独特作用,我们建立了Stat2基因敲除小鼠。这些小鼠对病毒感染高度敏感,对干扰素-IS没有部分反应。出乎意料的是,它们在干扰素-I刺激STATL激活和主要组织相容性复合体II(MHC-II)的正常调节方面表现出组织特异性差异。这些观察结果突出了I型干扰素在调节先天免疫和获得性免疫方面发挥的重要作用。为了了解干扰素-是如何调节它们的许多有效作用的,我们建议:
1.确定I型干扰素受体的STATS是如何激活的,包括组织特异性差异。
2.确定Stat2在调节巨噬细胞MHC-II表达中的独特作用
3.探讨SUMO化在调节干扰素刺激的STATS动力学中的作用。
英文摘要
DESCRIPTION (provided by applicant): Interferons (IFNs), first identified for their potent antiviral activity, can be divided into two major classes. Of these, type II or immune IFN (a.k.a. IFN-gamma) has earned much notoriety, but the type I IFNs (IFN-Is; e.g., IFN-alpha, IFN-beta, etc.) represent a much larger and complex family. Consistent with this, viruses have evolved numerous strategies to thwart IFN-I activity. More recently, IFN-Is have also achieved some celebrity with the recognition that they are the major effector cytokine secreted by plasmacvtoid dendritic cells (pDCs, a.k.a. "Natural IFN-I Producing Cells"). These IFN-Is then regulate aspects of both innate and adaptive immunity. There is also intriguing new evidence that IFN-Is and pDCs play an important role in the pathogenesis of Systemic Lupus Erythematosis (SLE).
Like other cytokines, IFN-Is induce their potent activity through the induction of new genes. Characterization of the ability of IFN-alpha to rapidly induce genes led to the identification of Stat1 and Stat2, the first two STAT transcription factors. These STATs are recruited to the type I IFN receptor (IFNAR) by unknown mechanisms, whereupon they become activated (by tyrosine phosphorylation), dimerize, translocate to the nucleus and activate genes. In contrast, IFN-gamma transduces its signals solely through Stat1, albeit with differing kinetics.
To determine the unique role Stat2 plays in the biological response to IFN-Is, Stat2 knockout mice were generated. These mice were highly susceptible to viral infection and partially unresponsive to IFN-Is. Unexpectedly, they exhibited tissue-specific differences in IFN-I stimulated Statl activation and a loss in the normal regulation of the Major Histocompatibility Complex class II (MHC-II). These observations highlight the important role type I IFNs play in regulating innate and adaptive immunity. To understand how IFN-Is mediate their many potent effects we propose to:
1. Determine how STATs are activated at the type I IFN receptor, including tissue specific differences.
2. Determine the unique role Stat2 exhibits in regulating MHC-II expression in macrophages
3. Explore the role SUMOylation may play in regulating the kinetics of IFN stimulated STATs.
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会议论文
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