The Roles ofNramp1andTnfaGenes in Nitric Oxide Production and Their Effect on the Growth ofSalmonella typhimuriumin Macrophages fromNramp1Congenic and Tumor Necrosis Factor-α-/-Mice

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Abstract
The macrophages from Nramp1 congenic mice and tumor necrosis factor (TNF)-α-/- mice were used to examine the functions of Nramp1 and Tnfa genes in nitric oxide (NO) production and Salmonella typhimurium infection. It was confirmed that the level of inducible NO synthase (iNOS)-mediated NO production in Nramp1r peritoneal macrophages was generally higher than that of Nramp1s macrophages after stimulation by interferon-γ (IFN-γ), lipopolysaccharide (LPS), and tumor necrosis factor-α (TNF-α) alone or in combination. Nramp1 mRNA expression in both Nramp1 congenic macrophages was constitutive notwithstanding cytokine stimulation. During infection with S. typhimurium strain 6203, Nramp1r macrophages produced a lower amount of NO because of an initial strong reaction and unsustained iNOS gene expression as compared with Nramp1s macrophages. An inhibitory effect of the Nramp1r gene on bacterial replication was also observed during the early stage of S. typhimurium infection, whereas the effect of TNF-α occurred later. NO production and iNOS expression in TNF-α-/- macrophages were not detected from the start of the bacterial infection or at 24 h after infection. We also observed that S. typhimurium strain 6203 grew more profoundly without TNF-α, especially in Nramp1s macrophages. These data, therefore, demonstrate that there is cooperation of the Nramp1 and Tnfa genes in NO production and a growth inhibitory effect in response to S. typhimurium infection.