Expression of functional receptor activity modifying protein 1 by airway epithelial cells with dysregulation in asthma

被引:20
作者
Bonner, Kandace [1 ,3 ,4 ]
Kariyawasam, Harsha H. [1 ,2 ,3 ,4 ]
Ali, F. Runa [2 ,3 ,4 ]
Clark, Peter [1 ,3 ,4 ]
Kay, A. Barry [1 ,3 ,4 ]
机构
[1] Univ London Imperial Coll Sci Technol & Med, Leukocyte Biol Sect, London SW7 2AZ, England
[2] Univ London Imperial Coll Sci Technol & Med, Dept Allergy & Clin Immunol, London SW7 2AZ, England
[3] Univ London Imperial Coll Sci Technol & Med, MRC, London SW7 2AZ, England
[4] Univ London Imperial Coll Sci Technol & Med, Asthma UK Ctr Allerg Mech Asthma, Natl Heart & Lung Inst, Fac Med, London SW7 2AZ, England
关键词
RAMP1; CGRP; asthma; epithelial cells; GENE-RELATED PEPTIDE; CALCITONIN-RECEPTOR; HYPERRESPONSIVENESS; RAMPS; IMMUNOREACTIVITY; ADRENOMEDULLIN; ANGIOGENESIS; INFLAMMATION; RELEASE; LINE;
D O I
10.1016/j.jaci.2010.08.013
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
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.)
引用
收藏
页码:1277 / U314
页数:10
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