IJPPP Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Int J Physiol Pathophysiol Pharmacol 2012;4(2):59-73.

Original Article
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

Stephen C Land

Centre for Cardiovascular and Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, University of
Dundee, Dundee, DD1 9SY, Scotland, UK

Received April 25, 2012; accepted May 27, 2012; Epub June 23, 2012; Published June 30, 2012

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 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: α-melanocyte stimulating hormone-derived tripeptide, KPV, melanocortin receptor, MC3R, γ-melanocyte stimulating
hormone (γ-MSH),  airway epithelium,  Chemokine signaling, asthma, inflammation

Address all correspondence to:
Dr. Land SC
Centre for Cardiovascular and Diabetes Medicine
Medical Research Institute, Ninewells Hospital and Medical School
University of Dundee, Dundee, DD1 9SY, Scotland, UK.
Tel: +44 (0)1382 496542; Fax: +44 (0) 1382 425554
E-mail: s.c.land@dundee.ac.uk