Abstract
Soluble immune complexes bind to unprimed neutrophils and generate intracellular Ca2+ transients but fail to activate the NADPH oxidase. Following priming of the neutrophils with either tumor necrosis factor alpha or granulocyte-macrophage colony-stimulating factor, stimulation of the cells with the soluble immune complexes leads to an enhanced Ca2+ signal and significant secretion of reactive oxidants. The enhanced Ca2+ signal observed in primed neutrophils results from the influx of Ca2+ from the external environment and is partly sensitive to tyrosine kinase inhibitors. This is in contrast to the Ca2+ signal observed in unprimed neutrophils, which arises from the mobilization of intracellular stores. When the surface expression of FcgammaRIIIb on primed neutrophils was decreased either through incubation with Pronase or phosphoinositide-specific phospholipase C, the extra enhanced Ca2+ mobilization seen in primed cells was significantly lowered, while the initial rise in intracellular Ca2+ was unaffected. Depletion of FcgammaRIIIb had no significant effect on the Ca2+ transients in unprimed neutrophils. Cross-linking FcgammaRII, but not FcgammaRIIIb, induced increases in intracellular Ca2+ in unprimed neutrophils, while cross-linking either of these receptors increased Ca2+ levels in primed neutrophils. The FcgammaRII-dependent intracellular Ca2+ rise in primed cells was unaffected by incubation in Ca2+-free medium, whereas the FcgammaRIIIb-dependent transient was significantly decreased when Ca2+ influx was prevented in Ca2+-free medium supplemented with EGTA. Cross-linking either FcgammaRII or FcgammaRIIIb in primed or unprimed cells failed to stimulate substantial levels of inositol 1,4,5-trisphosphate production. These results indicate that following stimulation of primed neutrophils with soluble immune complexes the enhanced Ca2+ mobilization observed is the result of a functional activation of the glycosylphosphatidylinositol-linked FcgammaRIIIb.
Highlights
Soluble immune complexes bind to unprimed neutrophils and generate intracellular Ca21 transients but fail to activate the NADPH oxidase
Cross-linking either FcgRII or FcgRIIIb in primed or unprimed cells failed to stimulate substantial levels of inositol 1,4,5-trisphosphate production. These results indicate that following stimulation of primed neutrophils with soluble immune complexes the enhanced Ca21 mobilization observed is the result of a functional activation of the glycosylphosphatidylinositol-linked FcgRIIIb
In this study we have investigated the mechanisms by which soluble immune complexes activate neutrophils via Fcg receptors
Summary
(Received for publication, November 21, 1996, and in revised form, March 12, 1997). From the School of Biological Sciences, Life Sciences Building, University of Liverpool, P. Soluble immune complexes bind to unprimed neutrophils and generate intracellular Ca21 transients but fail to activate the NADPH oxidase. Following priming of the neutrophils with either tumor necrosis factor a or granulocyte-macrophage colony-stimulating factor, stimulation of the cells with the soluble immune complexes leads to an enhanced Ca21 signal and significant secretion of reactive oxidants. Cross-linking either FcgRII or FcgRIIIb in primed or unprimed cells failed to stimulate substantial levels of inositol 1,4,5-trisphosphate production These results indicate that following stimulation of primed neutrophils with soluble immune complexes the enhanced Ca21 mobilization observed is the result of a functional activation of the glycosylphosphatidylinositol-linked FcgRIIIb. Neutrophils play a major role in host defense via the phagocytosis and destruction of pathogens during acute inflammation. These studies add new insights into the mechanisms by which cellular priming alters the functional responsiveness of neutrophils during inflammatory activation
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