FC-GAMMA-RIII-MEDIATED REGULATION OF HEMATOPOIESIS IN MURINE BONE-MARROW CELLS BY INTERLEUKIN-3 AND CD95 (FAS APO-1)/

The interleukin-3 (IL-3)-dependent murine bone marrow-derived cell lin e FDC-P2/185-4 (185-4) undergoes apoptosis when IL-3 is withdrawn from culture medium. Previous results from our studies indicated that a hi gh concentration of aggregated mouse IgG prevented apoptosis of 185-4 cells through Fc gamma RIII by an autocrine mechanism, producing IL-3. But after 24 hours, 185-4 cells expressed CD95 (Fas/Apo-1) on their s urfaces on stimulation via Fc gamma RIII. in addition, this CD95 was f unctional and apoptosis was induced by anti-CD95 monoclonal antibody ( MoAb). We investigated how these conflicting effects were induced by F c gamma RIII stimulation within the context of cell survival and death . The results showed that IL-3 was induced by calcium ionophore and th at the IL-3 induced by Fc gamma RIII stimulation was blocked by EGTA o r FK506, but not by staurosporine (protein kinase C [PKC] inhibitor), indicating the important role of calcium-calcineurin in this system. O n the other hand, the CD95 expression induced by Fc gamma RIII stimula tion was blocked by staurosporine, but not by EGTA or FK506, and phorb ol myristate acetate (PMA) induced CD95 expression in the same manner as Fc gamma RIII, indicating the involvement of PKC in the CD95 expres sion induced by Fc gamma RIII stimulation. Thus, Fc gamma RIII-mediate d stimulation even while promoting immediate survival of the bone marr ow cells, also triggers mechanisms that will facilitate their eventual deletion at the end of the response. These results suggest that a bal ance between cell survival and death is maintained to avoid unlimited cell growth caused by Fc gamma RIII-ligand interaction in hematopoiesi s during inflammation. (C) 1997 by The American Society of Hematology.