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.
|Number of pages||15|
|Journal||International Journal of Physiology, Pathophysiology and Pharmacology|
|Publication status||Published - 2012|
Land, S. C. (2012). 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. International Journal of Physiology, Pathophysiology and Pharmacology, 4(2), 59-73. http://www.ijppp.org/contents.html