Cross-Linking of Human Fc_#gamma#RIIIb Induces the Production of Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor by Polymorphonuclear Neutrophils

摘要

We have reported that human autoantibodies reacting with the polymorphonuclear neutrophil (PMN)-anchored Fc_#gamma#RIIIb (CD16) protect these cells from spontaneous apoptosis. In this study, we used anti-CD16 F(ab')_2 to delineate the mechanism(s) whereby the PMN life span is extended. As documented using four methods, CD16 cross-linking impeded spontaneous apoptosis, whereas anti-CD18F(ab')_2 exerted no effect. Incubation of PMNs with anti-CD16 prevented the up-regulation of #beta#_2 integrins, particularly CD11b, which is the #alpha#-chain of complement receptor type 3, but also CD18, which is its #beta#-chain, as well as CD11a and CD11c. Anti-CD16-conditioned supernatant of PMNs diminished the percentage of annexin V-binding fresh PMNs after another 18 h in culture, whereas the negative control anti-CD18 had no effect. The expression of mRNA for G-CSF and GM-CSF was induced by anti-CD16, followed by the release of G-CSF and G-CSF and GM-CSF in a dose-dependent manner. Anti-G-CSF and anti-GM-CSF mAbs abrogated the antiapoptotic effect of the related growth factors. The delay in apoptosis was accompanied by a down-regulated expression of Bax, and a partial reduction of caspase-3 activity. These data suggest an autocrine involvement of anti-CD16-induced survival factors in the rescue of PMNs from spontaneous apoptosis. Thus, apoptosis of aged PMNs can be modulated by signaling through Fc#gamma#RIIIb, which may occur in patients with PMN-binding anti-Fc#gamma#RIIIb autoantibodies.