INHIBITION BY INSOLUBLE IMMUNE-COMPLEXES OF BOTH CAPACITATIVE CA2+ ENTRY AND CA2+ MOBILIZATION BY CHEMOTACTIC AGONISTS IN HUMAN NEUTROPHILS

Insoluble immune complexes (IIC) stimulate human neutrophils by bindin g to their FcR. It is known that they are able to release Ca2+ from in tracellular stores but they induce little Ca2+ entry from the extracel lular medium, a dissociation that cannot be explained within the frame work of the capacitative model for Ca2+ entry, which is well establish ed for these cells. We show here that IIC induce a strong and long-las ting inhibition of the Ca2+ pathway activated by emptying the Ca2+ sto res (capacitative Ca2+ entry), which develops simultaneously with the activation of Ca2+ release from intracellular stores. This inhibition strongly resembles that previously described effected by FMLP and by p horbol dibutyrate, which seems to be mediated by phosphorylation. Inhi bition by IIC, however, differs from that induced by FMLP and phorbold ibutyrate in its lack of sensitivity to cytosolic-free calcium concent ration and in its different sensitivity to the protein kinase inhibito rs staurosporin and chelerythrine. It was also insensitive to the prot ein tyrosine kinase inhibitors genistein and herbimycin A. We also sho w that IIC inhibit Ca2+ mobilization induced by other agonists and tha t this inhibition is potentiated by the protein phosphatase inhibitor calyculin A. Our results therefore suggest that binding of IIC to the FcR activates a protein phosphorylation mechanism leading to a long-la sting inhibition of both capacitative Ca2+ entry and Ca2+ mobilization induced by other agonists such as FMLP, platelet-activating factor, o r leukotriene B-4.