Inhibition of cellular and systemic inflammation cues in human bronchial epithelial cells by melanocortin-related peptides

mechanism of KPV action and a role for MC3R agonists

    Research output: Contribution to journalArticle

    7 Citations (Scopus)

    Abstract

    Background/Aims: Chemokine signaling from airway epithelium regulates macrophage recruitment to the lung in inflammatory diseases such as asthma. This study investigates the mechanism by which the a-melanocyte stimulating hormone-derived tripeptide, KPV, and the agonist of the dominant melanocortin receptor in airway epithelium (MC3R), ?-melanocyte stimulating hormone (?-MSH), suppress inflammation in immortalised human bronchial airway epithelium. Methods: TNFa and rhino syncitial virus (RSV)-evoked nuclear factor-?B (NF?B) signaling was measured in immortalised human bronchial epithelial cells (16HBE14o-) in response to KPV and ?MSH. Cellular and systemic inflammatory signaling was measured by NF?B reporter gene and chemokine (IL8, eotaxin) secretion, respectively. Results: KPV and ?MSH evoked a dose-dependent inhibition of NF?B, matrix metalloproteinase-9 activity, IL8 and eotaxin secretion. The KPV effect was associated with its nuclear import, I?Ba stabilisation and suppressed nuclear translocation of YFP-tagged p65RelA. Competition assays revealed an interaction between KPV and the Imp- a3 binding site on p65RelA which may involve blockade of the importin-a armadillo domain 7 and 8. In contrast, the ?MSH anti-inflammatory effect required MC3R whose apical expression occurred in epithelium distributed along the length of the respiratory tree in vivo. Conclusion: KPV and ?MSH respectively suppress NF?B signalling in airway epithelium by: i) inhibition of p65RelA nuclear import and, ii) epithelial MC3R activation. Melanocortin peptides therefore provide a robust mechanism for targeting airway inflammation in lung disease.
    Original languageEnglish
    Pages (from-to)59-73
    Number of pages15
    JournalInternational Journal of Physiology, Pathophysiology and Pharmacology
    Volume4
    Issue number2
    Publication statusPublished - 2012

    Fingerprint

    Melanocortins
    Melanocyte-Stimulating Hormones
    Cues
    Epithelial Cells
    Inflammation
    Epithelium
    Peptides
    Cell Nucleus Active Transport
    Interleukin-8
    Chemokines
    Melanocortin Receptors
    Karyopherins
    Armadillos
    Matrix Metalloproteinase 9
    Reporter Genes
    Lung Diseases
    Inhibition (Psychology)
    Anti-Inflammatory Agents
    Asthma
    Macrophages

    Cite this

    @article{75e38642b53e48aa99375be3153aeacc,
    title = "Inhibition of cellular and systemic inflammation cues in human bronchial epithelial cells by melanocortin-related peptides: mechanism of KPV action and a role for MC3R agonists",
    abstract = "Background/Aims: Chemokine signaling from airway epithelium regulates macrophage recruitment to the lung in inflammatory diseases such as asthma. This study investigates the mechanism by which the a-melanocyte stimulating hormone-derived tripeptide, KPV, and the agonist of the dominant melanocortin receptor in airway epithelium (MC3R), ?-melanocyte stimulating hormone (?-MSH), suppress inflammation in immortalised human bronchial airway epithelium. Methods: TNFa and rhino syncitial virus (RSV)-evoked nuclear factor-?B (NF?B) signaling was measured in immortalised human bronchial epithelial cells (16HBE14o-) in response to KPV and ?MSH. Cellular and systemic inflammatory signaling was measured by NF?B reporter gene and chemokine (IL8, eotaxin) secretion, respectively. Results: KPV and ?MSH evoked a dose-dependent inhibition of NF?B, matrix metalloproteinase-9 activity, IL8 and eotaxin secretion. The KPV effect was associated with its nuclear import, I?Ba stabilisation and suppressed nuclear translocation of YFP-tagged p65RelA. Competition assays revealed an interaction between KPV and the Imp- a3 binding site on p65RelA which may involve blockade of the importin-a armadillo domain 7 and 8. In contrast, the ?MSH anti-inflammatory effect required MC3R whose apical expression occurred in epithelium distributed along the length of the respiratory tree in vivo. Conclusion: KPV and ?MSH respectively suppress NF?B signalling in airway epithelium by: i) inhibition of p65RelA nuclear import and, ii) epithelial MC3R activation. Melanocortin peptides therefore provide a robust mechanism for targeting airway inflammation in lung disease.",
    author = "Land, {Stephen C.}",
    note = "Copyright 2012 Elsevier B.V., All rights reserved.",
    year = "2012",
    language = "English",
    volume = "4",
    pages = "59--73",
    journal = "International Journal of Physiology, Pathophysiology and Pharmacology",
    issn = "1944-8171",
    publisher = "e-Century Publishing Corporation",
    number = "2",

    }

    TY - JOUR

    T1 - Inhibition of cellular and systemic inflammation cues in human bronchial epithelial cells by melanocortin-related peptides

    T2 - mechanism of KPV action and a role for MC3R agonists

    AU - Land, Stephen C.

    N1 - Copyright 2012 Elsevier B.V., All rights reserved.

    PY - 2012

    Y1 - 2012

    N2 - Background/Aims: Chemokine signaling from airway epithelium regulates macrophage recruitment to the lung in inflammatory diseases such as asthma. This study investigates the mechanism by which the a-melanocyte stimulating hormone-derived tripeptide, KPV, and the agonist of the dominant melanocortin receptor in airway epithelium (MC3R), ?-melanocyte stimulating hormone (?-MSH), suppress inflammation in immortalised human bronchial airway epithelium. Methods: TNFa and rhino syncitial virus (RSV)-evoked nuclear factor-?B (NF?B) signaling was measured in immortalised human bronchial epithelial cells (16HBE14o-) in response to KPV and ?MSH. Cellular and systemic inflammatory signaling was measured by NF?B reporter gene and chemokine (IL8, eotaxin) secretion, respectively. Results: KPV and ?MSH evoked a dose-dependent inhibition of NF?B, matrix metalloproteinase-9 activity, IL8 and eotaxin secretion. The KPV effect was associated with its nuclear import, I?Ba stabilisation and suppressed nuclear translocation of YFP-tagged p65RelA. Competition assays revealed an interaction between KPV and the Imp- a3 binding site on p65RelA which may involve blockade of the importin-a armadillo domain 7 and 8. In contrast, the ?MSH anti-inflammatory effect required MC3R whose apical expression occurred in epithelium distributed along the length of the respiratory tree in vivo. Conclusion: KPV and ?MSH respectively suppress NF?B signalling in airway epithelium by: i) inhibition of p65RelA nuclear import and, ii) epithelial MC3R activation. Melanocortin peptides therefore provide a robust mechanism for targeting airway inflammation in lung disease.

    AB - Background/Aims: Chemokine signaling from airway epithelium regulates macrophage recruitment to the lung in inflammatory diseases such as asthma. This study investigates the mechanism by which the a-melanocyte stimulating hormone-derived tripeptide, KPV, and the agonist of the dominant melanocortin receptor in airway epithelium (MC3R), ?-melanocyte stimulating hormone (?-MSH), suppress inflammation in immortalised human bronchial airway epithelium. Methods: TNFa and rhino syncitial virus (RSV)-evoked nuclear factor-?B (NF?B) signaling was measured in immortalised human bronchial epithelial cells (16HBE14o-) in response to KPV and ?MSH. Cellular and systemic inflammatory signaling was measured by NF?B reporter gene and chemokine (IL8, eotaxin) secretion, respectively. Results: KPV and ?MSH evoked a dose-dependent inhibition of NF?B, matrix metalloproteinase-9 activity, IL8 and eotaxin secretion. The KPV effect was associated with its nuclear import, I?Ba stabilisation and suppressed nuclear translocation of YFP-tagged p65RelA. Competition assays revealed an interaction between KPV and the Imp- a3 binding site on p65RelA which may involve blockade of the importin-a armadillo domain 7 and 8. In contrast, the ?MSH anti-inflammatory effect required MC3R whose apical expression occurred in epithelium distributed along the length of the respiratory tree in vivo. Conclusion: KPV and ?MSH respectively suppress NF?B signalling in airway epithelium by: i) inhibition of p65RelA nuclear import and, ii) epithelial MC3R activation. Melanocortin peptides therefore provide a robust mechanism for targeting airway inflammation in lung disease.

    UR - http://www.scopus.com/inward/record.url?scp=84863952469&partnerID=8YFLogxK

    M3 - Article

    VL - 4

    SP - 59

    EP - 73

    JO - International Journal of Physiology, Pathophysiology and Pharmacology

    JF - International Journal of Physiology, Pathophysiology and Pharmacology

    SN - 1944-8171

    IS - 2

    ER -