학술논문
Manipulation of dipeptidylpeptidase 10 in mouse and human in vivo and in vitro models indicates a protective role in asthma.
Document Type
Academic Journal
Author
Zhang Y; Genomics Medicine Section, National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK y.zhang@imperial.ac.uk c.dean@imperial.ac.uk.; Poobalasingam T; Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College London, London, SW7 2AZ, UK.; Yates LL; Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College London, London, SW7 2AZ, UK.; Walker SA; Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College London, London, SW7 2AZ, UK.; Taylor MS; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3, 7BN.; Chessum L; MRC Harwell Institute, Oxfordshire, OX11 0RD, UK.; Harrison J; MRC Harwell Institute, Oxfordshire, OX11 0RD, UK.; Tsaprouni L; Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK.; Adcock IM; Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK.; Lloyd CM; Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College London, London, SW7 2AZ, UK.; Cookson WO; Genomics Medicine Section, National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK.; Moffatt MF; Genomics Medicine Section, National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK.; Dean CH; Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College London, London, SW7 2AZ, UK y.zhang@imperial.ac.uk c.dean@imperial.ac.uk.; MRC Harwell Institute, Oxfordshire, OX11 0RD, UK.
Source
Publisher: Company of Biologists Ltd Country of Publication: England NLM ID: 101483332 Publication Model: Electronic Cited Medium: Internet ISSN: 1754-8411 (Electronic) Linking ISSN: 17548403 NLM ISO Abbreviation: Dis Model Mech Subsets: MEDLINE
Subject
Language
English
Abstract
We previously identified dipeptidylpeptidase 10 ( DPP10 ) on chromosome 2 as a human asthma susceptibility gene, through positional cloning. Initial association results were confirmed in many subsequent association studies but the functional role of DPP10 in asthma remains unclear. Using the MRC Harwell N-ethyl-N-nitrosourea (ENU) DNA archive, we identified a point mutation in Dpp10 that caused an amino acid change from valine to aspartic acid in the β-propeller region of the protein. Mice carrying this point mutation were recovered and a congenic line was established ( Dpp10 145D ). Macroscopic examination and lung histology revealed no significant differences between wild-type and Dpp10 145D/145D mice. However, after house dust mite (HDM) treatment, Dpp10 mutant mice showed significantly increased airway resistance in response to 100 mg/ml methacholine. Total serum IgE levels and bronchoalveolar lavage (BAL) eosinophil counts were significantly higher in homozygotes than in control mice after HDM treatment. DPP10 protein is present in airway epithelial cells and altered expression is observed in both tissue from asthmatic patients and in mice following HDM challenge. Moreover, knockdown of DPP10 in human airway epithelial cells results in altered cytokine responses. These results show that a Dpp10 point mutation leads to increased airway responsiveness following allergen challenge and provide biological evidence to support previous findings from human genetic studies. This article has an associated First Person interview with the first author of the paper.
Competing Interests: Competing interestsThe authors declare no competing or financial interests.
(© 2018. Published by The Company of Biologists Ltd.)
Competing Interests: Competing interestsThe authors declare no competing or financial interests.
(© 2018. Published by The Company of Biologists Ltd.)