This study was designed to determine the effector molecule responsible for the
tumor-inhibitory activity of rat neutrophils treated with rat recombinant
interferon gamma (rIFN-gamma) in vitro. The results show that
nitric oxide (NO) production by neutrophils is dependent on rIFN-gamma concentration, and that neutrophil-mediated
tumor cytostasis is in turn dependent on the amount of NO. NO production and
tumor cytostasis by rIFN-gamma-activated neutrophils were inhibited completely by N(G) monomethyl-
L-arginine (NGMMA), a specific competitive NO production inhibitor.
Tumor cytostasis was also inhibited by
oxyhemoglobin (HbO(2)), an NO scavenger. An extracellular
oxygen radical scavenger,
superoxide dismutase (SOD), was found to increase
tumor cell inhibition by rIFN-gamma-activated neutrophils by
a factor of 4. This SOD-enhanced cytostasis was not even inhibited by
catalase.
Tumor cytostasis was slightly increased by a
hydroxyl radical-(.
OH) scavenger,
dimethylthiourea (
DMTU), which did not affect NO production by rIFN-gamma-activated neutrophils. Our findings suggest that
tumor cytostasis of neutrophils activated by rIFN-gamma is mediated by
L-arginine-derived
nitrogen oxidation products, and that O(2)- produced by these neutrophils reduces NO-mediated
tumor cytostasis at low NO concentrations.