Restricted replication of Listeria monocytogenes in a gamma interferon-activated murine hepatocyte line.Infect Immun. 1995 Aug; 63(8):3187-95.II
The intracellular pathogen Listeria monocytogenes replicates mainly in resting macrophages and hepatocytes residing in infected tissues. Both innate and acquired resistance strongly depend on activation of listericidal capacities of macrophages by gamma interferon (IFN-gamma) produced by natural killer cells and T lymphocytes. In contrast to macrophages, hepatocytes have been considered to serve purely as a cellular habitat, prolonging survival of the pathogen in the host. By using an immortalized murine hepatocyte line, the relationship between L. monocytogenes and this cell type has been analyzed in more detail. Our data reveal that hepatocytes are able to eradicate listeriolysin-deficient (avirulent) L. monocytogenes but fail to control growth of listeriolysin-expressing (virulent) L. monocytogenes organisms. Following stimulation with IFN-gamma, hepatocytes gained the capacity to restrict growth of virulent L. monocytogenes, although less efficiently than the highly listericidal IFN-gamma-activated macrophages. Hepatocytes costimulated with a combination of IFN-gamma, interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) expressed the highest antilisterial activities. Although IFN-gamma-stimulated hepatocytes produced demonstrable levels of reactive nitrogen intermediates (RNI), the results of inhibition studies do not support a major role for these molecules in antilisterial hepatocyte activities. In contrast, inhibition of RNI produced by macrophages neutralized their antilisterial effects. IFN-gamma-stimulated, L. monocytogenes-infected hepatocytes expressed TNF-alpha mRNA, suggesting that they are a source of this cytokine during listeriosis. These studies suggest a novel function for hepatocytes in listeriosis: first, IFN-gamma-stimulated hepatocytes could contribute to listerial growth restriction in the liver, and second, through secretion of proinflammatory cytokines, they could promote phagocyte influx to the site of listerial growth.