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  • Title: Tumor necrosis factor alpha enhances the cytotoxicity induced by nitric oxide in cultured cerebral endothelial cells.
    Author: Zhu DY, Li R, Liu GQ, Hua WY.
    Journal: Life Sci; 2000 Feb 25; 66(14):1325-35. PubMed ID: 10755468.
    Abstract:
    It has been shown that independent sources of nitric oxide (NO) and the inflammatory cytokine tumor necrosis factor alpha (TNFalpha) contribute to the breakdown of the blood-brain barrier (BBB) in the pathogenesis of a number of brain disorders. However, the interaction of NO and TNFalpha has not been elucidated. The present study was designed to determine whether the toxicity induced by NO is altered by TNFalpha in brain capillary endothelial cells (BCECs), and if so, whether it is related to the generation of superoxide. TNFalpha (50-400 U/ml) did not produce toxicity until at a concentration of 800 U/ml. This toxic effect was completely blocked by copper-zinc superoxide dismutase (SOD)/catalase or N(omega)-nitro-L-arginine methyl ester (L-NAME) or oxyhemoglobin (HbO2). Sodium nitroprusside (SNP) reduced with 0.4 mM ascorbate (SNP/Vc) significantly increased Lactate dehydrogenase (LDH) efflux in a concentration-dependent manner. This cytotoxicity of SNP/Vc was also completely inhibited by SOD/catalase or HbO2. When SNP/Vc used in combination with 400 U/ml TNFalpha, a more remarkable LDH efflux was induced than SNP/Vc alone, even as little as 0.01 mM SNP/Vc was toxic, although a dose of 400 U/ml TNFalpha alone had no effect on LDH efflux. In addition, either 0.4 mM SNP/Vc and 800 U/ml TNFalpha alone or 0.4 mM SNP/Vc and 400 U/ml TNFalpha in combination significantly increased malondialdehyde (MDA) content, but nitric oxide synthase (NOS) activity was inhibited only by SNP/Vc and TNF in combination. These results suggest that TNFalpha enhances the toxicity of NO in BCECs and that at least part of this enhancement involves the generation of superoxide.
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