TY - JOUR T1 - Cysteinyl Leukotriene-1 Receptor Activation in a Human Bronchial Epithelial Cell Line Leads to Signal Transducer and Activator of Transcription 1-Mediated Eosinophil Adhesion JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1024 LP - 1030 DO - 10.1124/jpet.107.131649 VL - 325 IS - 3 AU - Mirella Profita AU - Angelo Sala AU - Anna Bonanno AU - Liboria Siena AU - Maria Ferraro AU - Rossana Di Giorgi AU - Angela M. Montalbano AU - Giusy D. Albano AU - Rosalia Gagliardo AU - Mark Gjomarkaj Y1 - 2008/06/01 UR - http://jpet.aspetjournals.org/content/325/3/1024.abstract N2 - We studied the effect of leukotriene D4 (LTD4) on a human bronchial epithelial cell line (16HBE) overexpressing the cysteinyl leukotriene (CysLT) 1 receptor (HBECysLT1R), looking at the associated signal transduction mechanisms as well as at effects on inflammatory cell adhesion. The results obtained showed that LTD4 increases the phosphorylation of extracellular signal-regulated protein kinase (ERK) 1/2 and of the signal transducer and activator of transcription 1 (STAT-1) in serine 727 (STAT-1Ser727), resulting in increased eosinophil adhesion to HBECysLT1R, associated with enhanced surface expression of intercellular adhesion molecule (ICAM) 1. Pretreatment with a CysLT1R-selective antagonist or with a selective inhibitor of protein kinase C (PKC) or with a selective inhibitor of the mitogen-activated protein kinase kinase (MEK) successfully suppressed both LTD4-induced STAT-1Ser727 phosphorylation and the associated increase in eosinophil adhesion. The use of the MEK inhibitor and of the selective CysLT1R antagonist in electrophoretic mobility shift assay experiments showed that LTD4 promotes the nuclear translocation of STAT-1 through the activation of ERK1/2 pathway. The key role of STAT-1 in leukotriene D4 transduction signaling was confirmed by RNA interference experiments, where silencing of STAT-1 expression abolished the effect of leukotriene D4 on eosinophil adhesion. In conclusion, for the first time, we provide evidence of the involvement of STAT-1 in the signal transduction mechanism of the CysLT1 receptor; phosphorylation of STAT-1, through PKC and ERK1/2 activation, causes enhanced ICAM-1 surface expression and eosinophil adhesion. Effective CysLT1R antagonism may therefore contribute to the control of the chronic inflammatory condition that characterizes human airways in asthma. The American Society for Pharmacology and Experimental Therapeutics ER -