Interleukin-2-activated rat natural killer cells express inducible nitric oxide synthase that contributes to cytotoxic function and interferon-gamma production
Mg. Cifone et al., Interleukin-2-activated rat natural killer cells express inducible nitric oxide synthase that contributes to cytotoxic function and interferon-gamma production, BLOOD, 93(11), 1999, pp. 3876-3884
Natural killer (NK) cells are large granular lymphocytes capable of destroy
ing cells infected by virus or bacteria and susceptible tumor cells without
prior sensitization and restriction by major histocompatability complex (M
HC) antigens, Their cytotoxic activity could be strongly enhanced by interl
eukin-2 (IL-2), Previous findings, even if obtained with indirect experimen
tal approaches, have suggested a possible involvement of the inducible nitr
ic oxide (iNOS) pathway in the NK-mediated target cell killing. The aim of
the present study was first to directly examine the induction of iNOS in IL
-2-activated rat NK cells isolated from peripheral blood (PB-NK) or spleen
(S-NK), and second to investigate the involvement of the iNOS-derived NO in
the cytotoxic function of these cells. Our findings clearly indicate the i
nduction of iNOS expression in IL-2-activated PB-NK and S-NK cells, as eval
uated either at mRNA and protein levels. Accordingly, significantly high le
vels of iNOS activity were shown, as detected by the L-arginine to L-citrul
line conversion in appropriate assay conditions. The consequent NO generati
on appears to partially account for NK cell-mediated DNA fragmentation and
lysis of sensitive tumor target cells, In fact, functional inhibition of iN
OS through specific inhibitors, as well as the almost complete abrogation o
f its expression through a specific iNOS mRNA oligodeoxynucleotide antisens
e, significantly reduced the lytic activity of IL-2-activated NK cells. Mor
eover, IL-2-induced interferon-gamma production appears also to be dependen
t at least in part, on iNOS induction, (C) 1999 by The American Society of
Hematology.