Nitric oxide is produced during TNF killing of U937A cells but does not contribute to the cytotoxic process.
Proinflammatory cytokines, including TNF, stimulate nitric-oxide free radical production in a variety of tissues through the induction of the enzyme nitric-oxide synthase. As free radicals are considered likely candidates in the cytotoxic action of TNF, we examined nitric oxide production in TNF-sensitive U937A and TNF-resistant U937A/R cells and its potential role in TNF-induced cytotoxicity. TNF stimulated U937A nitrite production through a process that was abolished by the competitive inhibitors of nitric-oxide synthase N-omega-nitro-L-arginine methyl ester (NAME) and N-G-monomethyl-L-arginine (NMMA) without inhibition of TNF-induced cytotoxicity. TNF also increased nitrite production in TNF-resistant U937A/R cells. In addition, the cytotoxic action of TNF was independent of L-arginine substrate availability. Thus, although cytokine-inducible nitric oxide production is emerging as an effective antitumour mechanism, here, TNF clearly exerted potent antitumour activity against U937A cells through a nitric-oxide-independent mechanism.
Yamanouchi Research Institute, Oxford, UK.
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C
Southern
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Matthews
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D016923:Cell Death; D004351:Drug Resistance; D006801:Humans; D006822:Hybrid Cells; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D001120:Arginine