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A P2X Ion Channel–Triggered NF-B Pathway Enhances TNF-–Induced IL-8 Expression in Airway Epithelial Cells

¹ GIGA-Research, Human Genetics Unit, University of Liège, Liège, Belgium

Correspondence and requests for reprints should be addressed to Cécile Oury, Ph.D., GIGA-Research, Human Genetics Unit, University of Liège, B34, 1 Avenue de l'hôpital, B-4000 Liège, Belgium. E-mail: cecile.oury{at}ulg.ac.be

Extracellular ATP, acting at P2Y and P2X receptors, has recently been shown to contribute to airway inflammation. The aim of our study was to investigate the molecular mechanisms involved in the ATP-dependent regulation of IL-8 production by airway epithelial cells. Treatment of human normal tracheal (NT)-1 cells with ATP or its two analogs, ,β-methylene ATP (,β-meATP) and 2'- and 3'-O-(4-benzoyl-benzoyl)-ATP (BzATP) activated NF-B through the IB kinase (IKK) complex, a process requiring Ca²⁺, calmodulin (CaM), and Ca²⁺/CaM-dependent kinase (CaMK), but independent from phospholipase C. ,β-meATP–induced IKK activation also occurred in the alveolar A549 cell line. Real-time RT-PCR revealed that NT-1 and A549 cells expressed P2X₄, P2X₅,and P2X₆ subtype mRNAs, whereas P2X₇ mRNAs were only detected in NT-1 cells. Polarized human primary nasal epithelial cells expressed all four P2X subtypes. Both ,β-meATP and BzATP caused Ca²⁺-dependent binding of phosphorylated p65 (S536) NF-B subunit to the endogenous IL-8 gene promoter in NT-1 cells. Although these agonists did not induce significant IL-8 gene expression by these cells, they markedly enhanced TNF-–induced NF-B activation, resulting in increased IL-8 expression and release. Application of ,β-meATP or BzATP at the apical side of polarized human primary nasal epithelial cells sufficed to cause CaMK-dependent IL-8 release by these cells. Thus, ATP promotes TNF-–elicited IL-8 expression through P2X ion channel–triggered Ca²⁺ entry, leading to CaMK-dependent IKK activation and binding of active p65 to IL-8 gene promoter.

Key Words: ATP • purinergic receptors • Ca²⁺/calmodulin–dependent kinase • NF-B • airway epithelia

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