Elucidation of molecular mechanisms and functional significance of cooperation between glucocorticoid receptor and NF-kB in the airways

摘要 皮质类固醇或糖皮质激素(GC)被广泛用于治疗炎症性呼吸道疾病，如 哮喘。尽管它们在临床上得到了广泛的应用，但其治疗的分子机制 GC的行动仍然不完全清楚。糖皮质激素通过与 糖皮质激素受体(GR)是一种核受体，然后移位到细胞核并调节基因 表情。GR的抗炎作用经典地归因于GR与其他 核因子-kB等转录因子在基因激活时抑制其转录活性 GR的表达与GCs的副作用有关。然而，最近的研究表明， GR可与核因子-kB协同激活基因表达。事实上，我们的芯片-序列研究发现了许多 在呼吸道上皮细胞中受GR和NF-kB协同调控的基因。此外，其中一些 协同激活的基因具有已知的抗炎作用，这些作用不依赖于糖皮质激素。 基于这一证据，我们假设gr和nf-kB协同诱导抗炎基因。 在呼吸道上皮细胞中参与GCs治疗作用的表达。我们将通过以下方式验证我们的假设 GR与NF-kB协同诱导SERPINA3的机制探讨及阐明 SERPINA3在过敏性呼吸道炎症中的作用。我们的具体目标是1)确定和定义 关键DNA序列元件介导GR和NF-kB在可能的SERPINA3增强子和2) 确定SERPINA3是否在体内抑制过敏性呼吸道炎症。通过这些目标，我们希望 证明GR和NFkB的合作代表了一条支持治疗作用的新途径 炎症性呼吸道疾病中GCs的表达。

Abstract Corticosteroids or glucocorticoids (GCs) are widely used to treat inflammatory airway diseases such as asthma. Despite their widespread use in the clinic, the molecular mechanisms underlying the therapeutic actions of GCs remain incompletely understood. Glucocorticoids mediate their actions by binding to the glucocorticoid receptor (GR) a nuclear receptor, which then translocates to the nucleus and regulates gene expression. Anti-inflammatory actions of GR have classically been attributed to GR binding to other transcription factors such as NF-KB and repressing their transcriptional activity while activation of gene expression by GR has been implicated in the side effects of GCs. Recent studies, however, have shown that GR can cooperate with NF-kB to activate gene expression. Indeed, our ChIP-Seq studies identified numerous genes that are regulated cooperatively by GR and NF-kB in the airway epithelium. In addition, some of these cooperatively activated genes have known anti-inflammatory actions that are glucocorticoid-independent. Based on this evidence, we hypothesize that GR and NF-kB cooperate to induce anti-inflammatory gene expression that contributes to therapeutic actions of GCs in airway epithelium. We will test our hypothesis by interrogating the mechanism of cooperation between GR and NF-kB to induce SERPINA3 and by elucidating the role of SERPINA3 in allergic airway inflammation. Our specific aims are 1) Identify and define the role of key DNA sequence elements mediating GR and NF-kB cooperation at a putative SERPINA3 enhancer and 2) Determine if SERPINA3 suppresses allergic airway inflammation in vivo. Through these aims we expect to demonstrate that GR and NFkB cooperation represents a novel pathway underpinning the therapeutic actions of GCs in inflammatory airway diseases.