Interferon-gamma prevents apoptosis in Epstein-Barr virus-infected natural killer cell leukemia in an autocrine fashion.
The significant function of cytokines includes maintenance of cell survival as well as induction of cell differentiation and/or proliferation. We demonstrate here that interferon-gamma (IFN-gamma) plays a role for progression of Epstein-Barr virus (EBV)-infected natural killer cell leukemia (NK leukemia) through maintaining cell survival. NK leukemia cells obtained from 7 patients had clonal episomal forms of EBV, indicating that the leukemic cells were of clonal origin. Although normal NK cells constitutively expressed Bcl-2, the EBV-infected NK leukemia cells lacked endogenous Bcl-2 expression and were hypersensitive to apoptosis in vitro. The addition of IFN-gamma to the culture significantly inhibited their spontaneous apoptosis without inducing cell proliferation or upregulation of Bcl-2. The NK leukemia cells constitutively secreted IFN-gamma, and the patients' sera contained a high concentration of IFN-gamma, levels that were high enough to prevent NK leukemia cells from apoptosis. Bcl-XL was not involved in the IFN-gamma-induced NK leukemia cell survival. These data suggest that the acquisition of IFN-gamma-mediated autocrine survival signals, other than Bcl-2 or BCL-XL, might be important for the development of EBV-infected NK leukemia.
Mizuno
S
S
First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Akashi
K
K
Ohshima
K
K
Iwasaki
H
H
Miyamoto
T
T
Uchida
N
N
Shibuya
T
T
Harada
M
M
Kikuchi
M
M
Niho
Y
Y
D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification*; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D007938:Leukemia / Q000276:immunology* / Q000821:virology*; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D015703:Antigens, CD; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma