Expression of functional receptor activity modifying protein 1 by airway epithelial cells with dysregulation in asthma
Expression of functional receptor activity modifying protein 1 by airway epithelial cells with dysregulation in asthma
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DOI：
10.1016/j.jaci.2010.08.013
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发表时间：
2010-12-01
影响因子：
14.2
通讯作者：
Kay, A. Barry
中科院分区：
文献类型：
--
作者：
Bonner, Kandace;Kariyawasam, Harsha H.;Kay, A. Barry
背景：上皮细胞降钙素基因相关肽（CGRP）的表达是激发性哮喘的一个特征。受体活性修饰蛋白1（Receptor activity modifying protein 1，RAMP 1）与降钙素受体样受体（calcitonin receptor-like receptor，CGRP 1）联合收割机结合形成CGRP 1受体。结果：炎性细胞因子可诱导BEAS-2B和A549上皮细胞释放CGRP，并诱导CGRP mRNA表达。RAMP 1在静息、未刺激的BEAS-2B和A549细胞中高度表达。CGRP诱导RAMP 1和IL-6产生的内化，这两者都被CGRP拮抗剂CGRP 8 -37抑制。通过炎性细胞因子激活BEAS-2B和A549细胞诱导CGRP分泌、CGRP与RAMP 1结合和RAMP 1内化，其被CGRP 8-37阻断。哮喘患者支气管活检组织中RAMP 1免疫反应性和RAMP 1 mRNA表达显著低于正常人（分别为P = 0.002和P = 0.007）。过敏原衍生的肽过敏性哮喘患者吸入的挑战产生了显着减少RAMP 1阳性上皮细胞的数量在responses（P = .027），但不nonresponses.Conclusion：受体活性修饰蛋白1表达的气道上皮细胞在培养和支气管活检正常人和内化后，上皮细胞活化通过自分泌反馈的CGRP。哮喘上皮细胞中RAMP 1表达明显失调，提示CGRP参与的通路受到持续刺激。（J Allergy Clin Immunol 2010;126：1277-83.）
Background: Epithelial cell expression of calcitonin generelated peptide (CGRP) is a feature of provoked asthma. Receptor activity modifying protein 1 (RAMP1) and the calcitonin receptor-like receptor combine to form the CGRP1 receptor.Objective: To determine whether functional RAMP1 is expressed by airway epithelial cells and whether there are alterations in asthma.Methods: BEAS-2B and A549 cells lines were studied by RTPCR, confocal microscopy, a quantitative immunofluorescence assay, and ELISA. Bronchial biopsies from normal subjects and subjects with asthma were examined by immunohistochemistry and in situ hybridization.Results: Inflammatory cytokines induced CGRP release and CGRP mRNA in BEAS-2B and A549 epithelial cell lines. RAMP1 was highly expressed by resting, unstimulated BEAS-2B and A549 cells. CGRP induced internalization of RAMP1 and IL-6 production, both of which were inhibited by the CGRP antagonist, CGRP8-37. Activation of BEAS-2B and A549 cells by inflammatory cytokines induced CGRP secretion, binding of CGRP to RAMP1, and RAMP1 internalization, which was blocked by CGRP 8-37. RAMP1 immunoreactivity and RAMP1 mRNA expression in bronchial biopsies from subjects with asthma were significantly lower than in normal subjects (P = .002 and P = .007, respectively). Inhalational challenge of atopic subjects with asthma with allergen-derived peptides produced a significant decrease in the numbers of RAMP1-positive epithelial cells in responders (P = .027) but not nonresponders.Conclusion: Receptor activity modifying protein 1 was expressed both by airway epithelial cells in culture and in bronchial biopsies from normal subjects and internalized after epithelial cell activation through autocrine feedback of CGRP. There is an apparent dysregulation of RAMP1 in asthmatic epithelium, suggesting continuous stimulation of pathways involving CGRP. (J Allergy Clin Immunol 2010;126:1277-83.)