QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.107.131649v1 325/3/1024    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Profita, M. Articles by Gjomarkaj, M. Search for Related Content PubMed PubMed Citation Articles by Profita, M. Articles by Gjomarkaj, M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH

CELLULAR AND MOLECULAR

Cysteinyl Leukotriene-1 Receptor Activation in a Human Bronchial Epithelial Cell Line Leads to Signal Transducer and Activator of Transcription 1-Mediated Eosinophil Adhesion

Institute of Biomedicine and Molecular Immunology, Italian National Research Council, Palermo, Italy (M.P., A.B., L.S., R.D.G., A.M.M., G.D.A., R.G., M.G.); Centre for Cardiopulmonary Pharmacology, Department of Pharmacological Sciences, University of Milan, Milan, Italy (A.S.); and Dipartimento di Anestesiologia, Rianimazione e delle Emergenze, University of Palermo, Palermo, Italy (M.F.)

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.

Address correspondence to: Dr. Angelo Sala, Centre for Cardiopulmonary Pharmacology, Department of Pharmacological Sciences, Via Balzaretti 9, 20133 Milan, Italy. E-mail: angelo.sala{at}unimi.it