Crystal‐induced neutrophil activation: X. Proinflammatory role of the tyrosine kinase Tec

Abstract

Objective. Monosodium urate monohydrate (MSU) crystals are among the most potent proinflammatory stimuli, and an innate immune inflammatory response to the crystal surface is involved in the pathogenesis of gouty arthritis. Release of the crystals into the joint cavity promotes an acute inflammation characterized by massive infiltration of neutrophils, which leads to tissue damage. The aim of the present study was to assess the involvement of the tyrosine kinase Tec in MSU crystal-initiated transduction events in human neutrophils.Methods. Immunoprecipitation and immunoblotting techniques were used for the cellular signaling studies. Chemotaxis and enzyme-linked immunosorbent assay techniques were used for the functional studies. Silencing of Tec expression using specific small interfering RNA was also performed.Results. MSU crystals induced the phosphorylation and activation of Tec in a Src-dependent manner. This activation was necessary for the MSU crystalinduced secretion of interleukin-1␤ (IL-1␤) and IL-8 and for the generation of chemotactic activity in supernatants of MSU crystal-stimulated neutrophils. In addition, colchicine, an effective drug for the treatment of gout, inhibited the MSU crystal-induced tyrosine phosphorylation of Tec, thus modulating its kinase activity.Conclusion. Our findings show that Tec is the principal kinase of the Tec family that plays a major role in the responses of human neutrophils to MSU crystals, which are likely to be involved in the initiation and perpetuation of gout. Our results suggest that the specific inhibition of Tec during the acute phase of MSU crystal-induced inflammation may be considered for the treatment of gouty arthritis.

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

“…The rapid liberation of a chemotactic factor by MSU crystalstimulated neutrophils might serve to modulate the neutrophil recruitment and responses during the initial stages of inflammation, and it may also play a role in the amplification of the inflammatory reaction that accompanies the gouty arthritis (11,44). We show that both the pharmacologic inhibition of PKC and the decreased expression of PKC␣ (which does not affect the expression of PKC␤) drastically inhibited the secretion of a chemotactic activity in supernatants of MSU crystal-stimulated neutrophils, which suggests a critical role of PKC␣ in the release of this factor that may be involved in the overactivation of human neutrophils in gouty inflammation.…”

“…The secretion of this factor, which is chemotactic, induces a mobilization of intracellular calcium, and increases the level of global tyrosine phosphorylation in freshly isolated neutrophils, was shown to be dependent on the tyrosine kinase Tec (44). We next examined the effect of the pharmacological inhibition (using Gö6976) or the molecular inhibition (using specific siRNAs) of conventional PKC on the generation of chemotactic activity in supernatants from MSU crystalstimulated neutrophils.…”

The Ubiquitin Ligase c-Cbl Down-Regulates FcγRIIa Activation in Human Neutrophils

“…Because of the difficulties associated with the transfection of human neutrophils, we opted for the use of a human neutrophil-like cellular model, the dibutyryl cAMP-dPLB-985 (59), to further test the involvement of c-Cbl in the stimulated ubiquitination and degradation of Fc␥RIIa. The responses of these cells to Fc␥RIIa crosslinking were characterized and found to closely resemble those of primary neutrophils (see Discussion).…”

Role of Hijama’ (Cupping Therapy) in the Management of Niqras (Gouty Arthritis)

“…MSU crystals are released into the joint cavity and are phagocytosed by synovial lining cells and infiltrating neutrophils. These cells release proinflammatory cytokines such as TNF-@ (Tumor necrosis factor), IL-1, IL-6, IL-8 which promote recruitment of additional neutrophils to the site of crystal deposition, thereby inducing an intense inflammatory response [1,14,15,16,37,38].…”