MECHANISMS OF TNFA INDUCED ICAM 1 IN AIRWAY EPITHELIUM

TNFA在气道上皮中诱导ICAM 1的机制

• 批准号: 2430606
• 负责人: THOMAS M KRUNKOSKY
• 金额: $ 3.12万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-10-12 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2430606
• 关键词: G protein; biological signal transduction; cell adhesion molecules; free radical oxygen; nuclear factor kappa beta; oxidation reduction reaction; pertussis toxin; phosphatidylcholines; phospholipase C; protein kinase C; respiratory epithelium; tissue /cell culture; tumor necrosis factor alpha

The overall hypothesis of this proposal is that the cytokine, tumor necrosis factor alpha (TNFalpha) plays an important role in the pathophysiology of airway diseases, such as asthma. We propose that TNFalpha interacts with airway epithelial cells provoking enhanced intercellular adhesion molecule-1 (ICAM-1) surface and gene expression which is mediated by reactive oxygen intermediates (ROI). This proposal will investigate the complex signal transduction cascade associated with TNFalpha - induced ICAM-1 gene and surface expression. The HYPOTHESIS to be addressed in this proposal is: TNFalpha binds to a specific cell-surface receptor on airway epithelial cells activating a Pertuss-toxin (PT) sensitive G protein linked to a phosphatidylcholine-specific phospholipase C (PC-PLC). Activation of PC- PLC results in production of diacylglycerol (DAG) which activates protein kinase C (PKC). Activation of PKC activates, in turn, the oxidant sensitive nuclear transcription factors activator protein-1 (AP-1) and nuclear factor kappa B (NFkappaB). This can occur directly and/or via PKC enhancement of intracellular ROI. Thus, interactions of PKC, transcription factors NFkappaB and AP-1, and the redox state of the cells results in enhanced ICAM-1 gene and surface expression. To address this hypothesis, normal human bronchial epithelial (NBHE) cells and the immortalized human bronchial epithelial cell line (BEAS-2B) will be utilized. These studies will elucidate mechanistic aspects of interactions between the pleuripotent cytokine TNFalpha: and airway epithelial cell ICAM-1 expression. Ultimately, this information will be helpful in developing new therapies for potentially life threatening pulmonary diseases.

该建议的总体假设是，细胞因子、肿瘤细胞因子。 坏死因子α（TNF α）在肿瘤的发生发展中起着重要作用。 呼吸道疾病的病理生理学，如哮喘。我们建议 TNF α与气道上皮细胞相互作用，引起增强的 细胞间粘附分子-1表面与基因表达 其由活性氧中间体（ROI）介导。这项建议 将研究复杂的信号转导级联与 TNF α诱导ICAM-1基因和表面表达。 本提案中要解决的假设是： TNF α与气道上皮细胞表面特异性受体结合 细胞激活连接到一个免疫球蛋白的百日咳毒素（PT）敏感性G蛋白， 磷脂酰胆碱特异性磷脂酶C（PC-PLC）。激活PC- PLC导致甘油二酯（DAG）的产生，其激活蛋白质 激酶C（PKC）。PKC的激活反过来激活氧化剂 敏感核转录因子激活蛋白-1（AP-1）， 核因子κ B（NF κ B）。这可以直接和/或通过PKC发生 增强细胞内ROI。因此，PKC， 转录因子NF κ B和AP-1，以及细胞的氧化还原状态 导致ICAM-1基因和表面表达增强。 为了解决这一假设，正常人支气管上皮（NBHE） 细胞和永生化人支气管上皮细胞系（BEAS-2B） 将被利用。这些研究将阐明 多能细胞因子TNF α与气道的相互作用 上皮细胞ICAM-1表达。最终，这些信息将被 有助于开发新的治疗方法， 肺部疾病。