Effects of interferon gamma on native human acute myelogenous leukaemia cells.
T cell targeting immunotherapy is now considered a possible strategy in acute myelogenous leukaemia (AML), and IFNgamma release may then contribute to the antileukaemic effects. We investigated the effects of IFNgamma on native human AML cells. Normal T cells could be activated to release IFNgamma in the presence of AML cells. Furthermore, high levels of CD119 (IFNgamma receptor alpha chain) expression were observed for all 39 patients examined. Receptor expression was decreased after exposure to exogenous IFNgamma, and receptor ligation caused Stat1 phosphorylation but no phosphorylation of the alternative messengers Erk1/2. The effect of exogenous IFNgamma on AML blast proliferation was dependent on the local cytokine network and IFNgamma (1) inhibited proliferation in the presence of exogenous IL1beta, GM-CSF, G-CSF and SCF; (2) had divergent effects in the presence of IL3 and Flt3 (65 patients examined); (3) inhibited proliferation in the presence of endothelial cells but had divergent effects in the presence of fibroblasts, osteoblasts and normal stromal cells (65 patients examined). IFNgamma increased stress-induced (spontaneous) in vitro apoptosis as well as cytarabine-induced apoptosis only for a subset of patients. Furthermore, IFNgamma decreased the release of proangiogenic CXCL8 and increased the release of antiangiogenic CXCL9-11. We conclude that IFNgamma can be released in the presence of native human AML cells and affect AML cell proliferation, regulation of apoptosis and the balance between pro- and antiangiogenic chemokine release.
Ersvaer
Elisabeth
E
Institute of Medicine, Section for Hematology, The University of Bergen and Haukeland University Hospital, Bergen, Norway. elisabeth.ersvar@med.uib.no
Skavland
Jørn
J
Ulvestad
Elling
E
Gjertsen
Bjørn Tore
BT
Bruserud
Øystein
Ø
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D007377:Interleukin-3 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007945:Leukemia, Lymphoid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D017471:Receptors, Interferon / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism; D000096743:Interferon gamma Receptor
D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D053583:Interleukin-1beta; D007377:Interleukin-3; D016209:Interleukin-8; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D051941:fms-Like Tyrosine Kinase 3; D000096743:Interferon gamma Receptor; C508606:CXCL8 protein, human; C080810:CXCL9 protein, human; C494079:STAT1 protein, human; C497970:FLT3 protein, human