Mechanisms of Immunosuppressive Actions of Glucocorticoids

糖皮质激素的免疫抑制作用机制

• 批准号: 7739481
• 负责人: INEZ ROGATSKY
• 金额: $ 38.24万
• 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/7739481
• 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; 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; Thyroiditis; Trans-Activators; Transcription Factor AP-1; Viral; Virus; Woman; Work; Yeasts; base; cell type; clinically relevant; cofactor; cytokine; design; disability; effective therapy; 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，位居十大病因之列 65 岁以下女性因疾病死亡的比例，是导致残疾的第四大原因。这也造成了严重的 经济负担以数十亿美元衡量。许多自身免疫性疾病的治疗依赖于葡萄糖 皮质激素（GC）抑制细胞因子的产生，例如干扰素（IFN）a/（J，与 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 的使用可以超过这些其他有效且负担得起的药物的益处。我们的长期目标是 确定健康和疾病中 GC 介导的免疫调节的关键观察者和机制，这是至关重要的 开发更具体的自身免疫疗法。 GC 信号通过配体依赖性 GC 受体 GR， 它招募辅助辅助因子来调节转录。具体来说，GR 依赖性 AP1 抑制 和 NFxB 反应基因解释了 GC 的某些抗炎活性。虽然额外的监管机构 必须介导 GC 诱导的深刻免疫抑制，但其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)l 作为 GR:NFKB 和 GR 的辅阻遏物： API 压制复合体。出乎意料的是，酵母 2 杂交筛选 GRIP1 抑制域相互作用蛋白 产生了干扰素调节因子 (IRF)3，这是 Toll- 下游先天免疫反应的关键效应子 样受体 (TLR)3/4 和 IFNp 的重要反式激活因子。该应用程序的目的是破译 GC 和 IRF3 之间的功能相互作用。我们假设 GRIP1 是 IRF3 辅助因子，在 IFN 中发挥作用 生产和自身免疫。我们进一步提出 GR 和 IRF3 竞争 GRIP1，使得激素- 激活GR，除了直接抑制APl/NFicB外，还使GRIP1远离IRF3；由此产生的 IRF3 依赖性转录的抑制可能是 GC 免疫的一个关键但尚未探索的组成部分 抑制。相反，响应细菌或病毒 TLR3/4 配体，IRF3 不仅增强细胞因子 直接转录，但也会从 GR:AP1 和 GR:NFx:B 抑制复合物中耗尽 GRIP1 促进有效的免疫反应。我们的具体目标是：(1) 剖析 GRIP1:IRF3 相互作用 体外、细胞内以及与 IFN 刺激反应元件结合的 IRF3 复合物中； (2) 证实 通过检查初级巨噬细胞中 GR 和 IRF3 之间的串扰来确定这种相互作用的相关性； (3) 确定 GRIP1 在 IRF3 转录中的作用，以及使用 GRIP1KO 小鼠在先天免疫反应中的作用 病毒，或体内的 dsRNA 和细菌 LPS。在无偏屏幕中发现的 GRIP1:IRF3 交互作用可能 具有广泛的生理意义。我们将探索 GRIP1 在免疫系统中的作用并破译 IRF3 靶基因的相关转录机制。这项工作应该提供一个分子 GC 和 IFN 之间功能拮抗的基础，并有助于将 IRF3 定义为 GR- 的新靶点 介导的免疫抑制，最终有助于设计更具体的自身免疫药物。