REGULATION OF HUMAN INTERLEUKIN-8 RECEPTORS

白介素8(IL-8)是一种重要的免疫调节因子。 许多炎症性疾病的反应，如呼吸窘迫 综合征、特发性肺纤维化、类风湿性关节炎和哮喘。 与其他促炎介质一样，吞噬细胞 对IL-8的反应是迁移到炎症部位，在那里它们成为 激活并参与宿主防御。这些功能是由 通过IL-8的特定细胞表面受体。IL-8的两种亚型 中性粒细胞的受体(IL-8RA和IL-8RB)已经被描述。两者都有 IL-8R亚型在IL-8刺激后变得不敏感。此外 IL-8R对同源脱敏和异源脱敏有交叉作用。 被其他化学引诱剂减敏的。到目前为止，人们对此知之甚少 IL-8R的调控机制。我们的研究表明，IL-1 8R介导的反应最容易受到交叉脱敏的影响 中性粒细胞中的其他化学诱导剂。这些研究还表明 受体/G蛋白远端的成分(S)可能参与 趋化受体交叉调节。当前的主要焦点 关于IL-8受体的调节及其机制的建议 它们会经历脱敏和交叉脱敏。首先，我们 将使用大鼠嗜碱性粒细胞白血病(RBL-2H3)细胞系，一种功能 稳定表达表位标记的IL-8受体的反应性细胞系 (ETIL-8RA和ETIL-8RB)，并阐明激动剂依赖和 IL-8R介导的反应调节中的独立磷酸化。 其次，我们将使用定向突变和缺失来识别特定的 IL-8R胞质结构域的氨基酸残基参与 调节受体功能。第三，我们将确定机制。 IL-8受体与其他受体之间的交叉磷酸化和脱敏 趋化受体在RBL-2H3中稳定共表达的研究 细胞。第四，我们将确定磷脂酶Cβ2的作用 (PLCbeta2)参与IL-8受体的交叉调节。 了解参与调控的分子机制 IL-8R及其受体在IL-8R交叉调节中的作用 趋化因子介导的炎症反应将有助于理解 炎症的控制以及许多炎症性疾病的病因 精神错乱。这些研究还将确定特定的目标 用于调节炎症的治疗药物的开发。

Interleukin-8 (IL-8) has been shown to be a key mediator of immunological reactions in many inflammatory disorders such as respiratory distress syndrome, idiopathic pulmonary fibrosis, rheumatoid arthritis and asthma. As is the case for other proinflammatory mediators, phagocytic leukocytes respond to IL-8 by migrating to sites of inflammation where they become activated and participate in host defense. These functions are mediated via specific cell surface receptors for IL-8. Two subtypes of IL-8 receptors (IL-8RA & IL-8RB) have been described in neutrophils. Both subtypes of IL-8R become desensitized upon IL-8-stimulation. In addition to homologous and heterologous desensitization, IL-8R are cross- desensitized by other chemoattractants. To date, little is known about the mechanism governing IL-8R regulation. Our studies have shown that IL- 8R-mediated responses are the most susceptible to cross-desensitization by other chemoattractants in neutrophils. These studies have also indicated that components(s) distal to the receptor/G-protein may be involved in chemoattractant receptor cross-regulation. The main focus of the present proposal is on the regulation of the IL-8 receptors and the mechanisms by which they undergo desensitization and cross-desensitization. First, we will use a rat basophilic leukemia (RBL-2H3) cell line, a functionally responsive cell line, to stably express epitope-tagged IL-8 receptors (ETIL-8RA and ETIL-8RB) and elucidate the role of agonist-dependent and independent phosphorylation in the regulation of IL-8R-mediated responses. Second, we will use directed mutagenesis and deletion to identify specific amino acid residues of the cytoplasmic domains of the IL-8R involved in modulating receptor functions. Third, we will determine the mechanisms of cross-phosphorylation and desensitization between IL-8 receptors and other chemoattractant receptors by stably coexpressing the receptors in RBL-2H3 cells. And fourth, we will determine the role of phospholipase C beta2 (PLCbeta2) in IL-8 receptor cross-regulation. Understanding the molecular mechanisms involved in the regulation of the IL-8R and the role played by these receptors in the cross-regulation of chemoattractant-mediated inflammatory responses will aid in understanding the control of inflammation as well as the etiology of many inflammatory disorders. These studies will also identify specific targets for the development of therapeutic drugs for the modulation of inflammation.