Interleukin 1 alpha and gamma-interferon induction of nitric oxide production from murine tumor-derived endothelial cells.
The role of nitric oxide (NO) in vascular function, host tumoricidal activity, and antiinflammatory effects is well documented. A number of cytokines induce NO from a variety of cell types. We have demonstrated in murine models that interleukin 1 alpha (IL-1 alpha) induces acute hemorrhagic necrosis, microvascular injury, and enhanced clonogenic tumor cell kill. Effects on the vasculature are observed only in tumor and not in normal tissues. Using methods established previously in our laboratory, murine tumor-derived and normal endothelial cells were cultured with IL-1 alpha, IFN-gamma, or IL-1 alpha/IFN-gamma at various doses with NO production quantitated through the measurement of nitrite by the Griess reaction. In tumor-derived endothelial cells, we demonstrated that neither cytokine alone was capable of inducing nitrite but that the combination of IL-1 alpha/IFN-gamma induced dose-dependent nitrite, with peak levels observed after 4 days incubation. When tumor-derived, normal yolk sac, mouse brain, or mouse aortic endothelial cells were treated with IL-1 alpha (100 units/ml)/IFN-gamma (10 units/ml), tumor-derived endothelial cells produced significantly more nitrite when compared to the normal endothelial cells. Nitrite production from IL-1 alpha/IFN-gamma was sensitive to the nitric oxide synthase inhibitors, NG-methyl-L-arginine or NG-nitro-L-arginine in a dose-dependent manner. In addition, dexamethasone significantly inhibited nitrite production from IL-1 alpha/IFN-gamma-treated, tumor-derived endothelial cells. These studies suggest that the antitumor activity of IL-1 alpha may be mediated through the production of NO from tumor-derived endothelial cells.
Chang
M J
MJ
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pennsylvania 15213, USA.
Modzelewski
R A
RA
Russell
D M
DM
Johnson
C S
CS
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply*; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D019335:Nitroarginine; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D019323:omega-N-Methylarginine
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D011994:Recombinant Proteins; D019335:Nitroarginine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine; D019001:Nitric Oxide Synthase