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

Stephen C Land¹ 

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

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

DOI  :  

学科分类：生理学与病理学

来源: e-Century Publishing Corporation

【 摘 要 】

Background/Aims:Chemokinesignalingfromairwayepitheliumregulatesmacrophagerecruitmenttothelungininflammatorydiseasessuchasasthma.Thisstudyinvestigatesthemechanismbywhichthe#945;-melanocytestimulatinghormone-derivedtripeptide,KPV,andtheagonistofthedominantmelanocortinreceptorinairwayepithelium(MC3R),#947;-melanocytestimulatinghormone(#947;-MSH),suppressinflammationinimmortalisedhumanbronchialairwayepithelium.Methods:TNF#945;andrhinosyncitialvirus(RSV)-evokednuclearfactor-#954;B(NF#954;B)signalingwasmeasuredinimmortalisedhumanbronchialepithelialcells(16HBE14o-)inresponsetoKPVand#947;MSH.CellularandsystemicinflammatorysignalingwasmeasuredbyNF#954;Breportergeneandchemokine(IL8,eotaxin)secretion,respectively.Results:KPVand#947;MSHevokedadose-dependentinhibitionofNF#954;B,matrixmetalloproteinase-9activity,IL8andeotaxinsecretion.TheKPVeffectwasassociatedwithitsnuclearimport,I#954;B#945;stabilisationandsuppressednucleartranslocationofYFP-taggedp65RelA.CompetitionassaysrevealedaninteractionbetweenKPVandtheImp-#945;3bindingsiteonp65RelAwhichmayinvolveblockadeoftheimportin-#945;armadillodomain7and8.Incontrast,the#947;MSHanti-inflammatoryeffectrequiredMC3Rwhoseapicalexpressionoccurredinepitheliumdistributedalongthelengthoftherespiratorytreeinvivo.Conclusion:KPVand#947;MSHrespectivelysuppressNF#954;Bsignallinginairwayepitheliumby:i)inhibitionofp65RelAnuclearimportand,ii)epithelialMC3Ractivation.Melanocortinpeptidesthereforeprovidearobustmechanismfortargetingairwayinflammationinlungdisease.(IJPPP1204002).

【 授权许可】

Unknown