Gamma-interferon inhibits Fc receptor II-mediated phagocytosis of tumor cells by human macrophages.
In vitro, monocyte-derived macrophages (MDM) are capable of efficient antibody-mediated phagocytosis of human nucleated tumor cells. These MDM express on their cell surface all three classes of Fc receptors for IgG (Fc gamma R). Fc gamma R specificity for murine antibody isotype allowed us to examine the phagocytic role of Fc gamma RII on control and gamma-interferon (IFN-gamma)-primed MDM. Monoclonal antibody 520C9 (IgG1) mediates phagocytosis through Fc gamma RII. This monoclonal antibody is directed against the HER-2/neu protooncogene product overexpressed on a variety of adenocarcinomas including the breast carcinoma cell line SK-BR-3. Our results showed that IFN-gamma treatment of differentiated MDM (days 8-12 in culture) inhibited Fc gamma RII-mediated phagocytosis in a dose-dependent manner with negative effects noted at doses as low as 0.1 units/ml. The percentage reduction in antibody-mediated phagocytosis observed following IFN-gamma priming (40 units/ml for 18 h) ranged from 23-89% of control. The inhibitory effect was evident when exposure to IFN-gamma was transient. Fc gamma RII expression was not altered by IFN-gamma treatment. In our model, IFN-gamma did not up-regulate or down-regulate HER-2/neu protein expression on our targets or affect the level of CD14 antigen expression on our MDM. Although IFN-gamma is a potent activator of monocytes/macrophages and can enhance certain tumoricidal mechanisms, our data show that antibody-dependent phagocytosis through the type II Fc receptor is inhibited by IFN-gamma priming. Nonspecific phagocytosis was not affected.
Backman
K A
KA
Department of Medicine, East Carolina University School of Medicine, Greenville, North Carolina 27858-4354.
Guyre
P M
PM
D000293:Adolescent; D001943:Breast Neoplasms; D004306:Dose-Response Relationship, Immunologic; D066246:ErbB Receptors / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D010587:Phagocytosis / Q000187:drug effects* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases; D011961:Receptors, Fc / Q000187:drug effects* / Q000502:physiology; D014407:Tumor Cells, Cultured
D066246:ErbB Receptors; D007371:Interferon-gamma; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011961:Receptors, Fc