MODULATION OF AIRWAY EPITHELIAL CELL CYTOKINE RECEPTOR FUNCTION

气道上皮细胞细胞因子受体功能的调节

• 批准号: 6103585
• 负责人: S LEVINE
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6103585
• 关键词: biological signal transduction; corticosteroids; cytokine; cytokine receptors; enzyme activity; human tissue; inhibitor /antagonist; interferon gamma; interleukin 1; interleukin 11; interleukin 13; interleukin 4; protein isoforms; protein kinase C; protein metabolism; receptor expression; respiratory epithelium; tissue /cell culture; tumor necrosis factor alpha

Airway epithelial cells express receptors for proinflammatory cytokines, such as tumor necrosis factor-a (TNF-a) and interleuken-1 (IL-1), and therefore represent target cells for autocrine or paracrine acting cytokines. Airway epithelial cells may modulate cytokine-mediated events via the shedding of cell surface receptors or by the production of receptor antagonists. Airway epithelial cells express the 55 kDa type I TNF receptor, which can be proteolytically cleaved to function as a soluble TNF binding protein. We have reported that protein kinase C activation by phorbol ester or IL-1a can induce shedding of the 55 kDa type I TNF receptor from human airway epithelial cells (HAEC), a condition associated with a decrease in total cellular 55 kDa type I TNF receptor numbers. Conversely, corticosteroids inhibit TNF receptor shedding and increase total cellular 55 kDa type I TNF receptor numbers. Studies are now under way to investigate the mechanisms underlying TNF receptor shedding and to identify the enzyme responsible for proteolytic cleavage. HAEC also express the type I intracellular isoform of the interleukin-1 receptor antagonist (icIL-1Ra type I). We have reported that corticosteroids induce icIL-1Ra type I mRNA and protein as a mechanism by which IL-1-mediated airway inflammatory events might be attenuated. Another manuscript has been completed describing the differential regulation of icIL-1Ra release from HAEC by corticosteroids and cytokines. IL-4, IL-13 and interferon-a induce icIL-1Ra type I release to the extracellular compartment, while corticosteroids inhibit release, thereby allowing for the accumulation of icIL-1Ra type I within the intracellular compartment. Additional studies are in progress to investigate the mechanism underlying icIL-1Ra type I release and to understand its role as a regulator of intracellular IL-1 bioactivity. An increased understanding of the mechanisms by which epithelial cells modulate responses to inflammatory cytokines may allow for the development of new therapeutic approaches to reduce airway inflammation.

气道上皮细胞表达 促炎细胞因子，如肿瘤坏死因子-a IL-1和TNF-α的表达，因此代表靶向IL-1的表达。 细胞自分泌或旁分泌作用细胞因子。气道上皮 细胞可以通过脱落细胞因子来调节精氨酸介导的事件。 细胞表面受体或通过产生受体拮抗剂。 气道上皮细胞表达55 kDa I型TNF受体， 其可被蛋白水解裂解以作为可溶性TNF发挥作用 结合蛋白我们已经报道了蛋白激酶C激活 佛波酯或IL-1a可诱导55 kDa I型 人气道上皮细胞（HAEC）的TNF受体， 与总细胞55 kDa I型减少相关的病症 TNF受体数量。相反，皮质类固醇抑制TNF 受体脱落并增加总细胞55 kDa I型TNF 受体数量目前正在进行研究， TNF受体脱落的潜在机制，并确定 负责蛋白水解裂解的酶。港灯亦表示， 白细胞介素-1受体的I型细胞内亚型 拮抗剂（icIL-1 Ra I型）。我们已经报道过皮质类固醇 诱导icIL-1 Ra I型mRNA和蛋白作为机制， IL-1介导的气道炎症事件可能是 减弱的另一份手稿已经完成， HAEC释放icIL-1 Ra的差异调节 皮质类固醇和细胞因子。IL-4、IL-13和干扰素-α诱导 icIL-1 Ra I型释放到细胞外室，而 皮质类固醇抑制释放，从而允许 icIL-1 Ra I型在细胞内的积聚 车厢正在进行更多的研究，以调查 icIL-1 Ra I型释放的机制，并了解其 作为细胞内IL-1生物活性的调节剂的作用。增加 了解上皮细胞调节 对炎性细胞因子的反应可能允许 开发新的治疗方法，以减少气道 炎症