REGULATION OF HUMAN INTERLEUKIN-8 RECEPTORS

白细胞介素-8（IL-8）已被证明是免疫调节的关键介质。 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，吞噬白细胞 通过迁移到炎症部位对IL-8作出反应， 激活并参与宿主防御。 这些功能是通过 通过IL-8的特异性细胞表面受体。 IL-8的两种亚型 在嗜中性粒细胞中已经描述了IL-8受体（IL-8 RA和IL-8 RB）。 两 IL-8 R的亚型在IL-8刺激后变得脱敏。 此外 IL-8 R与同源和异源脱敏有交叉作用， 对其他化学引诱物不敏感。 迄今为止，人们对 IL-8 R调节机制。 我们的研究表明，IL- 8 R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引诱物。 这些研究还表明， 受体/G蛋白远端的成分可能参与 化学引诱物受体交叉调节。 目前的主要焦点 建议是关于IL-8受体的调节和机制， 他们经历了脱敏和交叉脱敏。 一是 将使用大鼠嗜碱性白血病（RBL-2 H3）细胞系， 应答细胞系，以稳定表达表位标记的IL-8受体 （ETIL-8 RA和ETIL-8 RB）的作用，并阐明激动剂依赖性和 在IL-8 R介导的应答的调节中独立的磷酸化。 第二，我们将使用定向突变和缺失来鉴定特异性 IL-8 R的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 IL-8受体和其他受体之间的交叉磷酸化和脱敏 通过在RBL-2 H3中稳定共表达受体来诱导化学引诱物受体 细胞 第四，我们将确定磷脂酶C β 2 （PLC β 2）在IL-8受体交叉调节中的作用。 了解参与调节的分子机制， IL-8 R及其受体在IL-8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性疾病的病因 紊乱 这些研究还将确定 开发用于调节炎症的治疗药物。

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.