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Involvement of nitric oxide in target-cell lysis and DNA fragmentation
induced by murine natural killer cells
JG Filep, C Baron, S Lachance, C Perreault and JS Chan
Research Center, Maisonneuve-Rosemont Hospital, University of Montreal,
Montreal, Quebec, Canada.
Although it has been recognized for sometime that target cells destroyed by
natural killer (NK) cells die largely by apoptosis, the underlying
mechanisms are not fully understood. The aim of the present study was to
examine the role of nitric oxide (NO) in mediating murine NK-cell-induced
killing of YAC-1 lymphoma cells. NK calls induced extensive release of
125I-DNA and 51Cr from YAC-1 cells. The target killing ability of NK cells
was associated with an increased production of NO as measured by
concentrations of nitrite in the culture medium. That YAC-1 killing
resulted, in part, from the production of NO was confirmed by the
significant protection of cell lysis in L-arginine- depleted medium and by
approximately 30 % attenuation of cell lysis and DNA fragmentation by an
inhibitor of NO synthase, NG-nitro-L-arginine methyl ester (L-NAME) in a
culture medium containing 1 mmol/L L- arginine. Fluorescence microscopic
examination of YAC-1 cells showed the presence of changes in nuclear
morphology characteristic for apoptosis. The percentage of apoptotic cells
was markedly decreased by L-NAME. Further evidence for apoptosis is
provided by the specific pattern of internucleosomal DNA fragmentation both
in the absence and presence of L-NAME. During target-cell killing, an
increased oxidation of intracellularly trapped dichlorofluorescein was
observed in cells labeled with an antimouse NK-cell monoclonal antibody, as
measured by flow cytometry. These increases were effectively prevented by
L-NAME, but not W-13, an inhibitor of calmodulin. The ability of NO to
induce cell lysis and DNA fragmentation in YAC-1 cells was further
demonstrated by exposing tumor cells to chemically generated NO. Taken
together, these observations suggest a role for NO as one of the mediators
of NK-cell-mediated DNA fragmentation and cell lysis.
Volume 87,
Issue 12,
pp. 5136-5143,
06/15/1996
Copyright © 1996 by The American Society of Hematology
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