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(Journal of Leukocyte Biology. 2002;72:222-232.)
© 2002 by Society for Leukocyte Biology

Modulation of monocyte signaling and pore formation in response to agonists of the nucleotide receptor P2X₇

Mini Aga^*,, Christopher J. Johnson^*, Arlene P. Hart^*, Arturo G. Guadarrama, M. Suresh, John Svaren, Paul J. Bertics and Benjamin J. Darien^*

^* Departments of Medical,
Pathobiological, and
Comparative Bio-Sciences, School of Veterinary-Medicine, and
Department of Biomolecular Chemistry, University of Wisconsin, Madison

Correspondence: Dr. Benjamin J. Darien, Department of Medical Sciences, School of Veterinary-Medicine, University of Wisconsin, Madison, WI 53706-1102. E-mail: darienb{at}svm.vetmed.wisc.edu

Previous reports about the nucleotide receptor P2X₇, which exhibits ion channel and pore-forming activity and is known to promote IL-1ß processing, have centered largely on its role in macrophage function, whereas its participation in monocyte activity has been unclear. However, because extracellular ATP has been shown to affect monocytes with respect to IL-1ß release, we hypothesized that the P2X₇ receptor is also present and functional in a subpopulation of blood monocytes. Flow cytometric analysis revealed that about 70% of monocytes isolated from normal human donors expressed the P2X₇ receptor. Activation of P2X₇ receptor-associated pore formation by the agonist BzATP resulted in a 9- to 15-fold increase in the uptake of the membrane-impermeant fluorescent dye YO-PRO, and this dye uptake is markedly inhibited by the P2X₇ receptor antagonists KN-62 and oATP. Evidence supporting the presence of the functional P2X₇ receptor in monocytes also includes the observation that BzATP exposure results in a dose-dependent increase in the activation of mitogen-activated 2protein kinases and the nuclear translocation of the transcription factor NF-B in human monocytes and in THP-1 human monocytic cells. Furthermore, treatment of monocytes with BzATP induced the expression of cyclooxygenase-2 (COX-2) and tissue factor, which are two important endpoints that have not been previously shown to be regulated by nucleotide receptor action in monocytes. Together, these data indicate that a subpopulation of human monocytes express P2X₇ receptors that are functional with respect to pore formation, signal transduction, and mediator production, further supporting a key role for this nucleotide receptor in host immune responses.

Key Words: extracellular nucleotides • YO-PRO • COX-2 • tissue factor • NF-B

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