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OBJECTIVE: To determine the presence and characterize the activity of a soluble activation factor rapidly released by human neutrophils after stimulation with monosodium urate (MSU) crystals. METHODS: Supernatants from human neutrophils stimulated by MSU crystals for 5 to 60 min were tested for their ability to stimulate a chemotactic response, induce a mobilization of calcium, and increase the tyrosine phosphorylation levels in naive neutrophils. RESULTS: Supernatant from neutrophils stimulated <or= 15 min by MSU crystals was chemotactic for neutrophils, induced a mobilization of calcium, and increased the levels of tyrosine phosphorylation in fresh neutrophils. Generation of activity in the supernatant was independent of protein synthesis and was eliminated after digestion with trypsin. Leukotriene B4 (LTB4), platelet-activating factor (PAF), and formyl peptide receptor antagonists as well as neutralizing anti-interleukin 8 (IL-8) antibodies did not inhibit the chemotactic activity in the supernatant, although pertussis toxin did inhibit the mobilization of calcium observed in response to the supernatant. Stimulation of neutrophils with formyl-methionine-leucine-phenylalanine, IL-8, and LTB4 inhibited subsequent mobilization of calcium by the supernatant. CONCLUSION: There is rapid liberation of a potent activation signal from neutrophils after interaction with MSU crystals. This activation factor can further stimulate surrounding neutrophils and contribute to amplification of the inflammatory response induced by MSU crystals.