Crystal-induced neutrophil activation: X. Proinflammatory role of the tyrosine kinase Tec.
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 crystal-induced secretion of interleukin-1beta (IL-1beta) 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.


CONCLUSIONS
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.
Laval University, Quebec, Quebec, Canada.
Oana
O
Popa-Nita
Louis
L
Marois
Guillaume
G
Paré
Paul H
PH
Naccache
D002478:Cells, Cultured; D006073:Gout / Q000276:immunology; D006074:Gout Suppressants / Q000494:pharmacology; D006801:Humans; D009504:Neutrophils / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D014527:Uric Acid / Q000276:immunology
D006074:Gout Suppressants; D014527:Uric Acid; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases