Mechanisms of Immunosuppressive Actions of Glucocorticoids

糖皮质激素的免疫抑制作用机制

• 批准号: 7329803
• 负责人: INEZ ROGATSKY
• 金额: $ 38.61万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-15 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7329803
• 关键词: Accounting; Adrenal Cortex Hormones; Adverse effects; Affect; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmune thyroiditis; Autoimmunity; Benign; Binding; Biochemical; Biological Assay; Biological Response Modifiers; Cause of Death; Cell physiology; Cells; Complex; Cultured Cells; Cytokine Gene; Data; Development; Diabetes Mellitus; Disease; Double Stranded RNA Virus; Double-Stranded RNA; Economic Burden; Fostering; Foundations; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; Health; Hormones; Hybrids; IRF3 gene; Immune; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; In Vitro; Inflammatory; Interferons; Knock-out; Ligands; Link; Lupus; Measures; Mediating; Mediator of activation protein; Molecular; Monitor; Mus; NCOA2 gene; Nuclear Receptors; Numbers; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Physiological; Population; Production; Proteins; Recruitment Activity; Regulation; Repression; Response Elements; Role; Signal Pathway; Signal Transduction; Stimulus; Surface; Systemic Lupus Erythematosus; Testing; Therapeutic immunosuppression; Thyroiditis; Trans-Activators; Transcription Factor AP-1; Viral; Virus; Woman; Work; Yeasts; base; cell type; clinically relevant; cofactor; cytokine; design; disability; human IRF3 protein; human RIPK1 protein; human TLR3 protein; immunoregulation; in vivo; insight; interferon regulatory factor-3; macrophage; microbial alkaline proteinase inhibitor; novel; nuclear factor 1; promoter; receptor; response; steroid hormone receptor; transcription factor

Nearly 20%of the US population suffers from autoimmune diseases, which are among the top ten causes of death by disease for women under 65 and the 4th leading cause of disability. This also imposes a severe economic burden measured in billions ofdollars. Therapies for many autoimmune disorders rely on gluco- corticoids (GC)to inhibit the production of cytokines, such as interferons (IFN)a/ (J,which are intimately linked to the pathogenesis of lupus, autoimmune diabetes and thyroiditis. Yet, serious side effects associated with GC use can outweigh the benefits of these otherwise effective and affordable drugs. Our long-term goal is to identify the key viewers and mechanisms of GC-mediated immunomodulation in health and disease, which is essential for developing more specific therapiesfor autoimmunity. GC signal through a ligand-dependent GC receptor, GR, which recruits accessory cofactors to regulate transcription. Specifically, GR-dependent repression of AP1- and NFxB-responsive genes accounts for certain anti-inflammatory activities of GC. While additional regulators must mediate the profound GC-induced immunosuyyression, their identity and mechanisms ofaction are obscure. We established a nuclear receptor cofactor, GR-interacting protein (GRIP)l as a corepressor for GR:NFKB and GR: API repression complexes. Unexpectedly, a yeast 2-hybrid screen for GRIP1 Repression Domain interactors yielded Interferon Regulatory Factor (IRF)3, a key effector of innate immune responses downstream ofToll- like receptors (TLR)3/4 and an essential transactivator for IFNp. Theobjective ofthis application is to decipher the functional interaction between GC and IRF3. Wehypothesize that GRIP1 is an IRF3 cofactor with a role in IFN production and autoimmunity. Wefurther propose that GRand IRF3 competefor GRIP1 such that hormone- activated GR,in addition to directly repressing APl/NFicB,sequesters GRIP1 away from IRF3; the resulting inhibition of IRF3-dependent transcription is potentially a critical yet unexplored component of GC immuno- suppression. Conversely, in response to bacterial or viral TLR3/4 ligands, IRF3 not only enhances cytokine transcription directly, but also depletes GRIP1 from GR:AP1and GR:NFx:B repression complexes thereby promoting an effective immune response. Our Specific Aims are to: (1) dissect the GRIP1:IRF3 interaction in vitro, in cells and in IRF3 complexes bound at the IFN-Stimulated Response Elements; (2)corroborate the relevance of this interaction by examining the cross-talk between GRand IRF3 in primary macrophages; (3) identify the role of GRIP1 in IRF3 transcription and,using GRIP1KO mice, in innate immune responses to virus, or to dsRNA and bacterial LPS in vivo. The GRIP1:IRF3interaction uncovered in an unbiased screen may have a broad physiological significance. We will explore a role of GRIP1in the immune system and decipher associated transcriptional mechanisms operative at IRF3 target genes. This work should provide a molecular basis for a functional antagonism between GC and IFN, and help define IRF3 as a novel target for GR- mediated immunosuppression, ultimately aiding in the design of more specific drugs for autoimmunity.

近20%的美国人口患有自身免疫性疾病，这是十大原因之一 这是65岁以下妇女因疾病死亡的第四大原因，也是导致残疾的第四大原因。这也是一个严重的 经济负担以数十亿美元计算。许多自身免疫性疾病的治疗依赖于葡萄糖， 皮质激素（GC）抑制细胞因子如干扰素（IFN）α/β的产生，其与细胞因子的产生密切相关。 与狼疮、自身免疫性糖尿病和甲状腺炎的发病机制有关。然而，严重的副作用 GC的使用可能超过这些其他有效和负担得起的药物的好处。我们的长期目标是 确定GC介导的免疫调节在健康和疾病中的关键观察者和机制，这是至关重要的 for developing发展more specific具体therapies疗法for autoimmune自身免疫. GC信号通过配体依赖性GC受体GR， 其募集辅助辅因子来调节转录。具体地说，GR依赖的AP 1- NFxB反应基因解释了GC的某些抗炎活性。虽然其他监管机构 必须介导GC诱导的免疫抑制，但它们的身份和作用机制尚不清楚。我们 建立了核受体辅因子GR相互作用蛋白（GRIP）1作为GR：NF κ B和GR： API阻遏复合物。出乎意料的是，酵母双杂交筛选GRIP 1抑制结构域相互作用物 产生了干扰素调节因子（IRF）3，Toll下游先天免疫反应的关键效应子， 类受体（TLR）3/4和IFN β的必需反式激活因子。这个应用程序的目的是破译 GC和IRF 3之间的功能相互作用。我们假设GRIP 1是一个IRF 3辅因子，在IFN-γ中起作用。 生产和自身免疫。我们进一步提出，GR和IRF 3竞争GRIP 1，这样激素- 激活的GR除了直接抑制AP 1/NF κ B外，还将GRIP 1与IRF 3隔离; IRF 3依赖性转录的抑制是GC免疫抑制的潜在关键但尚未探索的组分， 镇压相反，在对细菌或病毒TLR 3/4配体的应答中，IRF 3不仅增强细胞因子 直接转录，但也从GR：AP 1和GR：NFx：B阻遏复合物中耗尽GRIP 1，从而 促进有效的免疫反应。我们的具体目标是：（1）解剖GRIP 1：IRF 3相互作用， 体外，在细胞中和在与IFN刺激的应答元件结合的IRF 3复合物中;（2）证实了 通过检查原代巨噬细胞中GR和IRF 3之间的串扰来确定这种相互作用的相关性;（3） 确定GRIP 1在IRF 3转录中的作用，并使用GRIP 1 KO小鼠，在先天性免疫应答中， 病毒，或dsRNA和细菌LPS在体内。在无偏筛选中发现的GRIP 1：IRF 3相互作用可能 具有广泛的生理意义。我们将探索GRIP 1在免疫系统中的作用， 相关的转录机制在IRF 3靶基因上起作用。这项工作应该提供一个分子 GC和IFN之间功能性拮抗作用的基础，并帮助将IRF 3定义为GR的新靶点- 介导的免疫抑制，最终有助于设计更特异性的自身免疫药物。