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Am J Physiol Lung Cell Mol Physiol 291: L734-L746, 2006. First published April 21, 2006; doi:10.1152/ajplung.00389.2005
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Nucleotides induce IL-6 release from human airway epithelia via P2Y2 and p38 MAPK-dependent pathways

Christelle D. Douillet,1 William P. Robinson, III,1 Peter M. Milano,1 Richard C. Boucher,2 and Preston B. Rich1

1Division of Trauma and Critical Care, Department of Surgery, and 2Department of Medicine, University of North Carolina, Chapel Hill, North Carolina

Submitted 9 September 2005 ; accepted in final form 18 April 2006

Extracellular nucleotides can mediate a variety of cellular functions via interactions with purinergic receptors. We previously showed that mechanical ventilation (MV) induces airway IL-6 and ATP release, modifies luminal nucleotide composition, and alters lung purinoceptor expression. Here we hypothesize that extracellular nucleotides induce secretion of IL-6 by small airway epithelial cells (SAEC). Human SAEC were stimulated with nucleotides in the presence or absence of inhibitors. Supernatants were analyzed for IL-6 and lysates for p38 MAPK activity by ELISA. RNA was analyzed by real-time RT-PCR. Rats (n = 51) were randomized to groups as follows: control, small-volume MV, large-volume MV, large-volume MV-intratracheal apyrase, or small-volume MV-intratracheal adenosine 5'-O-(3-thiotriphosphate) (ATP{gamma}S). After 1 h of MV, bronchoalveolar lavage fluid was analyzed for ATP and IL-6 by luminometry and ELISA. ATP and ATP{gamma}S increased SAEC IL-6 secretion in a time- and dose-dependent manner, an effect inhibited by apyrase. Agonists were ranked in the following order: ATP{gamma}S > ATP = UTP > ADP = adenosine > 2-methylthio-ADP = control. SB-203580, but not U-0126 or JNK1 inhibitor, decreased nucleotide effects. Additionally, nucleotides induced p38 MAPK phosphorylation. Inhibitors of Ca2+ signaling, phospholipase C, transcription, and translation decreased IL-6 release. Furthermore, nucleotides increased IL-6 expression. In vivo, large-volume MV increased airway ATP and IL-6 concentrations. IL-6 release was decreased by apyrase and increased by ATP{gamma}S. Extracellular nucleotides induce P2Y2-mediated secretion of IL-6 by SAEC via Ca2+, phospholipase C, and p38 MAPK-dependent pathways. This effect is dependent on transcription and translation. Our findings were confirmed in an in vivo model, thus demonstrating a novel mechanism of nucleotide-induced IL-6 secretion by airway epithelia.

cytokine; inflammation; purine; purinergic; ventilator-associated lung injury; interleukin-6; mitogen-activated protein kinase


Address for reprint requests and other correspondence: P. B. Rich, Division of Trauma and Critical Care, Dept. of Surgery, Univ. of North Carolina at Chapel Hill, 4008 Burnett-Womack, Chapel Hill, NC 27599-7228 (e-mail: chip_rich{at}med.unc.edu)




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