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Crystal-Induced Neutrophil Activation: XI. Implication and Novel Roles of Classical Protein Kinase C¹

Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du Centre Hospitalier de l’Université Laval, and Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada

Monosodium urate (MSU) crystals are among the most potent proinflammatory stimuli, and an innate immune inflammatory response to the crystal surface is involved in the pathology of gouty arthritis. Furthermore, MSU crystals have recently been identified as danger signals able to induce the maturation of dendritic cells. Release of the crystals into the joint cavity promotes an acute inflammation characterized by a massive infiltration of neutrophils that leads to tissue damage. Protein kinase C (PKC) represents a family of serine/threonine kinases that play central signaling roles in multiple cellular responses. This family of kinases is divided into three subfamilies based on second messenger requirements: conventional (or classical), novel, and atypical. Despite their role in signal transduction, very little is known about the involvement of the PKC family in the inflammatory reaction induced by MSU crystals. In the present study, we show that MSU crystals activate conventional PKC isoforms, and that this activation is necessary for the MSU crystal-induced degranulation and generation of a chemotactic activity in the supernatants of MSU crystal-stimulated human neutrophils. Evidence is also obtained that the tyrosine kinase Syk is a substrate of PKC and that the PKC-mediated serine phosphorylation of Syk is necessary to its interaction with the regulatory subunit of PI3K kinases (p85) and thus to the subsequent activation of these lipid kinases. These results suggest novel means of modulating neutrophil responses (through the specific regulation of PKC) during the acute phase of MSU crystal-induced inflammation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Grant 5R01AR052614-03 from the Arthritis Society and the National Institutes of Health. O.P.-N. and S.P. are recipients of the Canadian Arthritis Network Graduate Award. P.H.N. holds the Canada Research Chair on the Physiopathology of the Neutrophil.

² O.P.-N. and S.P. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Paul H. Naccache, Centre de Recherche en Rhumatologie et Immunologie du Centre de Recherche du Centre Hospitalier de l’Université Laval, Room T1-49, 2705 Boulevard Laurier, Québec City, Québec G1V 4G2, Canada. E-mail address: paul.naccache{at}crchul.ulaval.ca

⁴ Abbreviations used in this paper: MSU, monosodium urate; PKC, protein kinase C; DFP, diisopropylfluorophospate.