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: 2456670
• 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/2456670
• 关键词: biological signal transduction; corticosteroids; cytokine; cytokine receptors; enzyme activity; 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 pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1), and therefore represent target cells for autocrine or paracrine acting cytokines. Airway epithelial cells may modulate cytokine-mediated events by shedding 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-1b can induce shedding of the 55 kDa type I TNF receptor from human airway epithelial cells (HAEC), which is associated with decreased 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 under way to investigate the mechanisms underlying TNF receptor shedding and identify the enzyme responsible for proteolytic cleavage. HAEC also express the type I intracellular isoform of the IL-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-g induce icIL-IRa type I release to the extracellular compartment, while corticosteroids inhibit release, thereby allowing icIL-1Ra type I to accumulate within the intracellular compartment. Additional studies are in progress to investigate the mechanism underlying icIL-1Ra type I release and understand its role as a regulator of intracellular IL-11 bioactivity. An increased understanding of the mechanisms by which epithelial cells modulate responses to inflammatory cytokines may allow new therapeutic approaches to reduce airway inflammation to be developed.

气道上皮细胞表达促炎受体 细胞因子如肿瘤坏死因子-α（TNF-α）和 白细胞介素-1（IL-1），因此代表 自分泌或旁分泌作用的细胞因子。气道上皮细胞可能 通过脱落细胞表面受体调节精氨酸介导的事件 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，其可以是 蛋白水解裂解，作为可溶性TNF结合蛋白发挥作用 蛋白我们已经报道了蛋白激酶C的激活， 佛波酯或IL-1b可诱导55 kDa I型TNF的脱落 人气道上皮细胞（HAEC）的受体， 与总细胞55 kDa I型TNF受体减少相关 号码相反，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。 研究正在进行中，以调查TNF的潜在机制 受体脱落，并确定负责 蛋白水解裂解。HAEC还表达I型细胞内 IL-1受体拮抗剂的同种型（icIL-1 Ra I型）。我们有 报道了皮质类固醇诱导icIL-1 Ra I型mRNA， 蛋白作为IL-1介导的气道炎症的机制 事件可能会减弱。另一份手稿已经完成 描述了从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-g 诱导icIL-IRa I型释放至细胞外区室， 而皮质类固醇抑制释放，从而使icIL-1 Ra I型在细胞内区室中积累。 其他研究正在进行中以探讨其机制 潜在的icIL-1 Ra I型释放，并了解其作为 细胞内IL-11生物活性的调节剂。增加 了解上皮细胞调节 对炎性细胞因子的反应可能允许新的治疗方法 减少气道炎症的方法有待开发。