Popa-Nita Oana, Rollet-Labelle Emmanuelle, Thibault Nathalie, Gilbert Caroline, Bourgoin Sylvain G, Naccache Paul H
Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du CHUQ, Department of Medicine, Faculty of Medicine, Laval University, Québec, Canada.
J Leukoc Biol. 2007 Sep;82(3):763-73. doi: 10.1189/jlb.0307174. Epub 2007 May 29.
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.
尿酸单钠（MSU）晶体在人体关节中的沉积会引发极其急性的炎症反应，即通常所说的痛风，其特征是中性粒细胞大量浸润。MSU晶体与人类中性粒细胞及炎症介质的直接相互作用对于痛风发作的诱导和持续至关重要。MSU晶体与中性粒细胞之间的物理相互作用引发的细胞内信号转导事件取决于特定酪氨酸激酶（特别是Src和Syk）的激活。此外，PI-3K可能也参与其中。本研究调查了PI-3K家族在介导人类中性粒细胞对MSU晶体反应中的作用。所得结果表明，MSU晶体与人类中性粒细胞的相互作用通过一种依赖酪氨酸激酶Syk的机制导致Ia类PI-3K的激活。我们还发现，与源自MSU晶体刺激的人类中性粒细胞的非离子型去污剂P-40不溶性部分相关的p85量有所增加。此外，MSU晶体诱导形成一种包含p85和Syk的复合物，这是由Src家族激酶介导的。最后，也获得了证据表明MSU晶体对PI-3K的激活是调节人类中性粒细胞磷脂酶D激活和脱颗粒的关键因素。后一种反应可能与痛风患者发生的关节和组织损伤有关。
