We have previously reported that neutrophilic granulocytes rapidly release part 
of their Fc gamma RIII from the plasma membrane upon in vitro activation, 
probably by proteolytic cleavage. In plasma and other body fluids, released or 
soluble Fc gamma RIII has been found in considerable amounts. In the present 
study, neutrophils were kept in maintenance culture for 18 to 24 hours. Forty 
percent of the neutrophils completely lost Fc gamma RIII, and the remainder of 
the cells showed a 60% decrease in Fc gamma RIII expression on their surface. 
Released Fc gamma RIII was detected in the culture supernatant. Nevertheless, 
more than 90% of the cells was viable as judged by hydrolysis of fluorescein 
diacetate. The presence of interferon gamma, granulocyte colony-stimulating 
factor, or granulocyte-macrophage colony-stimulating factor, but not 
interleukin-3 (IL-3), IL-6, or IL-8, in the culture medium increased the number 
of cells that still expressed Fc gamma RIII. We found that this loss of Fc gamma 
RIII was not the result of cell activation but correlated strongly with 
apoptosis. The Fc gamma RIII-negative subpopulation exhibited typical 
morphologic changes, such as nuclear condensation and DNA fragmentation. 
Furthermore, this subpopulation appeared to have acquired the property of 
binding Annexin V, a calcium-dependent, phospholipid-binding protein with high 
affinity for phosphatidylserine. The external exposure of this phospholipid by 
cells has been reported to occur during apoptosis. The property of Annexin V 
binding was not shared by the nonapoptotic, Fc gamma RIII-positive 
subpopulation. In this respect, we identified binding of Annexin V as an 
convenient marker for apoptotic cells. Our results indicate that soluble Fc 
gamma RIII in body fluids might be derived for a large part from neutrophils 
undergoing apoptosis in the tissues.