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A more recent version of this article appeared on September 1, 2007

Published online before print May 29, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0307174

Received for publication March 19, 2007.
Revised April 24, 2007.
Accepted for publication April 30, 2007.

Article

Crystal-induced neutrophil activation. IX. Syk-dependent activation of class Ia phosphatidylinositol 3-kinase

Oana Popa-Nita , Emmanuelle Rollet-Labelle , Nathalie Thibault , Caroline Gilbert , Sylvain G. Bourgoin , and Paul H. Naccache @

Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du CHUQ, Department of Medicine, Faculty of Medicine, Laval University, Québec, Canada

@ To whom correspondence should be addressed. E-mail: Paul.Naccache{at}crchul.ulaval.ca.


  Abstract

The deposition of monosodium urate (MSU) crystals in the joints of humans leads to an extremely acute, inflammatory reaction, commonly known as gout, characterized by a massive infiltration of neutrophils. Direct interactions of MSU crystals with human neutrophils and inflammatory mediators are crucial to the induction and perpetuation of gout attacks. The intracellular signaling events initiated by the physical interaction between MSU crystals and neutrophils depend on the activation of specific tyrosine kinases (Src and Syk, in particular). In addition, PI-3Ks may be involved. The present study investigates the involvement of the PI-3K family in the mediation of the responses of human neutrophils to MSU crystals. The results obtained indicate that the interaction of MSU crystals with human neutrophils leads to the stimulation of class Ia PI-3Ks by a mechanism that is dependent on the tyrosine kinase Syk. We also found an increase in the amount of p85 associated with the Nonidet P-40-insoluble fraction derived from MSU crystal-stimulated human neutrophils. Furthermore, MSU crystals induce the formation of a complex containing p85 and Syk, which is mediated by the Src family kinases. Finally, evidence is also obtained indicating that the activation of PI-3Ks by MSU crystals is a critical element regulating phospholipase D activation and degranulation of human neutrophils. The latter response is likely to be involved in the joint and tissue damage that occurs in gouty patients.

Key Words: inflammation • gout • PI(3 • 4 • 5)P3 • phospholipase D • degranulation • tyrosine phosphorylation






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