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1 Physiology, Temple University Medical School, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: spk{at}temple.edu.
Nucleotides are released during vascular injury from activated platelets and broken cells, which could stimulate human neutrophils. In this study, we characterized the P2Y receptors and investigated the functional effects of extracellular nucleotides on human neutrophils. Pharmacological characterization using selective agonists and pertussis toxin revealed that human neutrophils express only functional P2Y2 receptors. However, P2Y2 receptor agonists ATP or UTP caused intracellular Ca2+ increases in isolated human neutrophils with an EC50 of 1 µM, but failed to cause release of primary granules from human neutrophils. ATP and UTP were equally potent in causing elastase release from human neutrophils in the presence of exogenous soluble fibrinogen, whereas ADP and UDP were without effect. We investigated whether nucleotides depend on generated arachidonic acid metabolites to cause degranulation. However, phenidone and MK-886, inhibitors of the 5-lipoxygenase pathway, failed to block nucleotide-induced intracellular calcium mobilization and elastase release. ATP and UTP caused activation of p38 MAPK and Erk 1/2 in human neutrophils. In addition, the inhibitors of MAPK pathway, SB203580 and U0126 inhibited nucleotide-induced elastase release. We conclude that fibrinogen is required for nucleotide-induced primary granule release from human neutrophils through the P2Y2 receptor without a role for arachidonic acid metabolites. Both Erk 1/2 and p38 MAPK play an important role in nucleotide-induced primary granule release from human neutrophils.
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