Endothelial Cell Production of Nitrogen Oxides in Response to Interferon in Combination With Tumor Necrosis Factor, Interleukin-1, or Endotoxin

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Abstract
Clinical studies using biological response modifiers in cancer therapy have shown that the major dose-limiting toxic effects are hypotension and diffuse microvascular leakage. The cause and pathophysiology of this hypotension remains unknown. Previous experiments have demonstrated that a number of cell types, including endothelial cells, neu-trophils, and macrophages, can secrete a potent hypotensive agent—endothelium-derived relaxing factor, which has recently been identified as nitric oxide. In this study, we tested interferon γ, tumor necrosis factor, interleukin-1, in-terleukin-2, muramyl dipeptide, and endotoxin for their effects on production of nitrogen oxides by endothelial cells. Interferon y, in combination with tumor necrosis factor, interleukin-1 (IL-1), or endotoxin, induced murine brain endothelial cells to secrete nitrites (20–45 μ M within 48 hr), which are breakdown products of nitric oxide. Nitrite production was blocked by incubation of endotheliai cells in medium without L-arginine, a substrate for nitric-oxide synthase. Accumulation of nitrites was also inhibited by addition of NG-monomethyl-L-arginine (l-NMMA), which acts as a competitive inhibitor of this enzyme. The inhibitory effects of l-NMMA were reversed by addition of excess L-arginine. These results suggest ( a ) that endothelial cells produce nitric oxide in response to immunomod-ulators and ( b ) that endothelial cell-derived nitric oxide plays a role in the development of hypotension in patients treated with tumor necrosis factor or interleukins. Furthermore, administration of substrate analogues such as l-NMMA may favorably alter the toxicity associated with these immunomodulators and result in a higher maximum tolerated dose, with subsequent improvement in the antitumor activity. J Natl Cancer Inst 82: 772–brief-report776, 1990]

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