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Cytokine-induced apoptosis of human natural killer cells identifies a novel
mechanism to regulate the innate immune response
ME Ross and MA Caligiuri
Department of Hematologic Oncology and Bone Marrow Transplantation, Roswell
Park Cancer Institute, Buffalo, NY 14263, USA.
Interferon-gamma (IFN-gamma) is critical for an effective innate immune
response against infection. A combination of interleukins (ILs) derived
from activated T cells (IL-2) and monocytes (IL-12), or monocytes alone
(IL-15 and IL-12), induces optimal production of IFN-gamma from natural
killer (NK) cells. The mechanism by which human NK cells downregulate their
production of IFN-gamma is unknown. Here we show that the same cytokines
that induce human NK cell IFN-gamma production subsequently induce
apoptosis of the NK cells. Fas, bcl-2, or bax do not appear to be involved
in this process. The mechanism of cytokine-induced apoptosis of human NK
cells appears to involve NK cell production of tumor necrosis factor-alpha
(TNF-alpha). Neutralization of TNF-alpha or inhibition of TNF-alpha binding
to the p80 TNF-alpha receptor partially inhibited apoptosis. Transforming
growth factor-beta, which inhibits cytokine-induced NK cell production of
IFN-gamma and TNF-alpha, also decreased cytokine-induced NK cell apoptosis.
Costimulation of a CD3- CD56+ NK leukemia cell line with IL-2 and IL-12 or
IL-15 and IL-12 induced apoptosis in vitro, which increased when combined
with a chemotherapeutic agent. In summary, costimulation of human NK cells
via the IL-2 receptor and the IL-12 receptor induces significant IFN-gamma
production, followed by NK cell apoptosis and a decline in IFN-gamma
production. Hence, cytokines that activate this innate immune response may
also serve to limit it via apoptosis. This novel observation may have
implications for the regulation of the innate immune response during
infection, the toxicity of combination cytokine therapy, and the treatment
of NK cell leukemia.
Volume 89,
Issue 3,
pp. 910-918,
02/01/1997
Copyright © 1997 by The American Society of Hematology
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