Published online before print February 22, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1206758

Received for publication December 22, 2006.
Revised February 1, 2007.
Accepted for publication February 1, 2007.

Article

Extracellular nucleotides mediate LPS-induced neutrophil migration in vitro and in vivo

Filip Kukulski ^*, Fethia Ben Yebdri ^*, Julie Lefebvre ^*, Michel Warny , Philippe A. Tessier , and Jean Sévigny ^*@

Centres de Recherche en *Rhumatologie et Immunologie and Infectiologie, Centre Hospitalier Universitaire de Québec, Université Laval, Québec, Canada; and Acambis, Inc., Cambridge, Massachusetts, USA

^@ To whom correspondence should be addressed. E-mail: jean.sevigny{at}crchul.ulaval.ca.

Abstract

Extracellular nucleotides are emerging as important inflammatory mediators. Here, we demonstrate that these molecules mediate LPS-induced neutrophil migration in vitro and in vivo. Apyrase, a nucleotide scavenger, reduced the ability of LPS-stimulated monocytes to recruit neutrophils, as assayed using a modified Boyden chamber. This effect resulted from the inhibition of IL-8 release from monocytes. Furthermore, LPS-induced IL-8 release by monocytes was attenuated significantly by P2Y₆ receptor antagonists, RB-2 and MRS2578. Reciprocally, UDP, the selective P2Y₆ agonist, induced IL-8 release by monocytes. As for LPS, the media of UDP-stimulated monocytes were chemotactic for neutrophils; IL-8 accounted for 50% of neutrophil migration induced by the media of LPS- or UDP-treated monocytes in transendothelial migration assays. It is important that in the murine air-pouch model, extracellular nucleotides were instrumental in LPS-induced neutrophil migration. Altogether, these data imply that LPS induces the release of nucleotides from monocytes and that by autocrine stimulation, the latter molecules regulate neutrophil migration caused by Gram-negative bacteria, suggesting a proinflammatory role of extracellular nucleotides in innate immunity.

Key Words: inflammation • monocyte • IL-8 • P2 receptor

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