Nitric oxide is an effector molecule in inhibition of tumor cell growth by rIFN-gamma-activated rat neutrophils.
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.
Yamashita
T
T
Department of Immunology and Parasitology, Yamagata University School of Medicine, Japan. tyamashi@med.id.yamagata-u.ac.jp
Uchida
T
T
Araki
A
A
Sendo
F
F
D000818:Animals; D002374:Catalase / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003601:Cytotoxicity Tests, Immunologic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D008297:Male; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D010108:Oxyhemoglobins / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins; D013482:Superoxide Dismutase / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000473:pathology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D010108:Oxyhemoglobins; D011994:Recombinant Proteins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; C038983:1,3-dimethylthiourea; D002374:Catalase; D013482:Superoxide Dismutase; D013890:Thiourea