Human NK cells express endothelial nitric oxide synthase, and nitric oxideprotects them from activation-induced cell death by regulating expression of TNF-alpha
K. Furuke et al., Human NK cells express endothelial nitric oxide synthase, and nitric oxideprotects them from activation-induced cell death by regulating expression of TNF-alpha, J IMMUNOL, 163(3), 1999, pp. 1473-1480
Although NO appears important in rodent immune responses, its involvement i
n the human immune system is unclear, We report that human NK cells express
constitutive endothelial NO synthase mRNA and protein, but not detectable
levels of inducible NO synthase. They produce NO following activation by co
culture with target cells or cross-linking with anti-CD16 mAb, and producti
on is increased in the presence of IL-2, N-monomethyl-L-arginine (L-NMA), a
NOS inhibitor, partially inhibited NK cell lysis of four different target
cells (<40% inhibition at 500 mu M L-NMA), but not granule release followin
g coculture with target cells, or Fas ligand induction following cross-link
ing with anti-CDl6 mAb, However, L-NMA augmented apoptosis of NK cells indu
ced by activation through CD16 ligation or coculture with K562. An NO donor
, S-nitroso-N-acetylpenicillamine (SNAP), suppressed apoptosis of NK cells
induced by CD16 cross-linking or coculture with target cells, suggesting th
at endogenous NO production is involved in protection of NK cells from acti
vation-induced apoptosis, thereby maintaining NK activity. SNAP also suppre
ssed, and L-NMA enhanced, expression of TNF-alpha, reported to be involved
in activation-induced NK cell death, in response to CD16 cross-linking. Sup
pression of anti-CD16-induced apoptosis by SNAP was reversed by the additio
n of rTNF-alpha, DNA-binding activity of the transcription factor, NF-AT, w
hich is involved in TNF-alpha induction upon ligation of CD16, was inhibite
d by SNAP and enhanced by L-MMA, Our results suggest that down-regulation o
f TNF-alpha expression, possibly due to suppression of NF-AT activation, is
a mechanism by which endogenous NO protects NK cells from activation-induc
ed apoptosis, and maintains lytic capacity.