CONTROL OF IL-6 BY THROMBIN IN LUNG FIBROBLASTS

凝血酶对肺成纤维细胞中 IL-6 的控制

• 批准号: 6625240
• 负责人: Jayarama B Gunaje
• 金额: $ 17.52万
• 依托单位: ICOGENEX CORPORATION
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-14 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6625240
• 关键词: JAK kinase; biological signal transduction; fibroblasts; inflammation; interleukin 6; lung injury; mitogen activated protein kinase; serine proteinases; thrombin; tissue /cell culture; transcription factor; transforming growth factors

Alpha-Thrombin and interleukin-6 (IL-6) play important roles in inflammation, tissue repair and wound healing. Their cellular responses are mediated via activation of signal transduction pathways. While alpha- thrombin mediates its effects through numerous signaling intermediates including mitogen-activated protein (MAP) kinases, IL-6 acts via stimulation of the JAK-STAT (Janus kinase-Signal Transducers and Activators of Transcription) pathway. In primary human lung fibroblast cultures and established cell lines, we recently demonstrated that alpha- thrombin, through a MAP kinase 1-dependent mechanism, inhibits IL-6 induced tyrosine phosphorylation of Stat3 protein. Stat3 is a member of STAT family of transcription factors, and its activation by tyrosine phosphorylation is a critical event in IL-6 induced signaling. Alpha- Thrombin's capacity to inhibit IL-6-induced signaling defines a new role for this multi-functional serine protease. Transforming growth factor-beta also inhibits IL-6 induced signaling in lung fibroblast indicating that crosstalk also involves other agonists implicated in the pathogenesis of lung injury and repair. Our working hypothesis is that alpha-thrombin interferes with IL-6- induced signaling at multiple steps, mediated by the actions kinases/phosphatases. In this study, utilizing biochemical and molecular approaches, we will elucidate the mechanism by which alpha-thrombin inhibits IL-6-induced JAK-STAT signaling in lung fibroblasts, and identify IL-6 induced genes inhibited by alpha-thrombin via this crosstalk. This proposal will enhance our understanding of signaling mechanisms by which alpha-thrombin and IL-6 are locally expressed in the alveolar space during lung injury, elucidation of this regulatory pathway could suggest novel strategies to prevent or attenuate pulmonary inflammation and/or fibrosis.

α-凝血酶和白细胞介素 6 (IL-6) 在炎症、组织修复和伤口愈合中发挥重要作用。它们的细胞反应是通过信号转导途径的激活来介导的。 α-凝血酶通过包括丝裂原激活蛋白 (MAP) 激酶在内的多种信号传导中间体介导其作用，而 IL-6 通过刺激 JAK-STAT（Janus 激酶信号转导器和转录激活器）途径发挥作用。在原代人肺成纤维细胞培养物和建立的细胞系中，我们最近证明α-凝血酶通过MAP激酶1依赖性机制抑制IL-6诱导的Stat3蛋白酪氨酸磷酸化。 Stat3 是转录因子 STAT 家族的成员，其通过酪氨酸磷酸化激活是 IL-6 诱导信号转导中的关键事件。 Alpha-凝血酶抑制 IL-6 诱导信号传导的能力定义了这种多功能丝氨酸蛋白酶的新作用。转化生长因子-β 还抑制肺成纤维细胞中 IL-6 诱导的信号传导，表明串扰还涉及与肺损伤和修复发病机制有关的其他激动剂。我们的工作假设是，α-凝血酶在多个步骤中干扰 IL-6 诱导的信号传导，由激酶/磷酸酶的作用介导。在本研究中，我们将利用生化和分子方法阐明α-凝血酶抑制肺成纤维细胞中IL-6诱导的JAK-STAT信号传导的机制，并通过这种串扰鉴定α-凝血酶抑制IL-6诱导的基因。该提议将增强我们对肺损伤期间肺泡腔局部表达α-凝血酶和IL-6的信号传导机制的理解，阐明这一调节途径可能会提出预防或减轻肺部炎症和/或纤维化的新策略。