Nitric oxide inhibits exocytosis of cytolytic granules from lymphokine-activated killer cells.
NO inhibits cytotoxic T lymphocyte killing of target cells, although the precise mechanism is unknown. We hypothesized that NO decreases exocytosis of cytotoxic granules from activated lymphocytes. We now show that NO inhibits lymphokine-activated killer cell killing of K562 target cells. Exogenous and endogenous NO decreases the release of granzyme B, granzyme A, and perforin: all contents of cytotoxic granules. NO inhibits the signal transduction cascade initiated by cross-linking of the T cell receptor that leads to granule exocytosis. In particular, we found that NO decreases the expression of Ras, a critical signaling component within the exocytic pathway. Ectopic expression of Ras prevents NO inhibition of exocytosis. Our data suggest that Ras mediates NO inhibition of lymphocyte cytotoxicity and emphasize that alterations in the cellular redox state may regulate the exocytic signaling pathway.
Ferlito
Marcella
M
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Irani
Kaikobad
K
Faraday
Nauder
N
Lowenstein
Charles J
CJ
D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000378:metabolism*; D005089:Exocytosis / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D015979:Killer Cells, Lymphokine-Activated / Q000166:cytology / Q000378:metabolism*; D016131:Lymphocyte Subsets; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism; D009603:Nitroso Compounds / Q000378:metabolism; D010084:Oxidation-Reduction; D015398:Signal Transduction / Q000502:physiology; D018631:ras Proteins / Q000378:metabolism
D017252:CD3 Complex; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide; D018631:ras Proteins