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

Abstract: The deposition of monosodium urate (MSU) crystals in the joints of humans leads to an extremely acute, inflammatory reaction, com-monly known as gout, characterized by a massive infiltration of neutrophils. Direct interactions of MSU crystals with human neutrophils and inflam-matory mediators are crucial to the induction and perpetuation of gout attacks. The intracellular sig-naling 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 in-volvement of the PI-3K family in the mediation of the responses of human neutrophils to MSU crys-tals. The results obtained indicate that the interac-tion of MSU crystals with human neutrophils leads to the stimulation of class Ia PI-3Ks by a mecha-nism 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 neu-trophils. Furthermore, MSU crystals induce the formation of a complex containing p85 and Syk, which is mediated by the Src family kinases. Fi-nally, 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 re-sponse is likely to be involved in the joint and tissue damage that occurs in gouty patients. J. Leukoc