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Published online before print February 23, 2005

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(Journal of Leukocyte Biology. 2005;77:958-965.)
© 2005 by Society for Leukocyte Biology

Stimulation of P2X receptors enhances lipooligosaccharide-mediated apoptosis of endothelial cells

Matt J. Sylte^*, Chris J. Kuckleburg^*, Thomas J. Inzana, Paul J. Bertics and Charles J. Czuprynski^*,1

^* Department of Pathobiological Sciences, School of Veterinary Medicine, and
Department of Biomolecular Chemistry, School of Medicine, University of Wisconsin, Madison; and
Center for Molecular Medicine and Infectious Diseases, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg

¹Correspondence: Department of Pathobiological Sciences, School of Veterinary Medicine, 2015 Linden Drive, Madison, WI 63706. E-mail: czuprync{at}svm.vetmed.wisc.edu

Exposure of endothelial cells to lipid A-containing molecules, such as lipopolysaccharide (LPS) or lipooligosaccharide (LOS), causes the release of purinergic compounds [e.g., adenosine 5'-triphosphate (ATP)] and can lead to apoptosis. The P2X family of purinergic receptors (e.g., P2X₇) has been reported to modulate LPS signaling events and to participate in apoptosis. We investigated the role that P2X receptors play in the apoptosis that follows exposure of bovine endothelial cells to Haemophilus somnus LOS. Addition of P2X inhibitors, such as periodate-oxidized ATP (oATP) or pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid tetrasodium, significantly reduced LOS-induced apoptosis. Incubation of endothelial cells with apyrase, which degrades ATP, diminished LOS-induced apoptosis of endothelial cells. Concomitant addition of P2X agonists [e.g., 2',3'-(4-benzoyl)-benzoyl ATP or ATP] to LOS-treated endothelial cells significantly enhanced caspase-3 activation. The P2X antagonist oATP significantly blocked caspase-8 but not caspase-9 activation in LOS-treated endothelial cells. Together, these data indicate that stimulation of P2X receptors enhances LOS-induced apoptosis of endothelial cells, possibly as a result of endogenous release of ATP, which results in caspase-8 activation.

Key Words: purinergic receptor • ATP

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