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

Int J Physiol Pathophysiol Pharmacol. 2012;4(2):59-73. Epub 2012 Jun 23.


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 α-melanocyte stimulating hormone-derived tripeptide, KPV, and the agonist of the dominant melanocortin receptor in airway epithelium (MC3R), γ-melanocyte stimulating hormone (γ-MSH), suppress inflammation in immortalised human bronchial airway epithelium.

Methods: TNFα and rhino syncitial virus (RSV)-evoked nuclear factor-κB (NFκB) signaling was measured in immortalised human bronchial epithelial cells (16HBE14o-) in response to KPV and γMSH. Cellular and systemic inflammatory signaling was measured by NFκB reporter gene and chemokine (IL8, eotaxin) secretion, respectively.

Results: KPV and γMSH evoked a dose-dependent inhibition of NFκB, matrix metalloproteinase-9 activity, IL8 and eotaxin secretion. The KPV effect was associated with its nuclear import, IκBα stabilisation and suppressed nuclear translocation of YFP-tagged p65RelA. Competition assays revealed an interaction between KPV and the Imp-α3 binding site on p65RelA which may involve blockade of the importin-α armadillo domain 7 and 8. In contrast, the γMSH anti-inflammatory effect required MC3R whose apical expression occurred in epithelium distributed along the length of the respiratory tree in vivo.

Conclusion: KPV and γMSH respectively suppress NFκB 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.

Keywords: KPV; MC3R; airway epithelium; asthma; chemokine signaling; inflammation; melanocortin receptor; α-melanocyte stimulating hormone-derived tripeptide; γ-melanocyte stimulating hormone (γ-MSH).