Localization of tumor necrosis factor-stimulated DNA synthesis in the liver

Tumor necrosis factor and other cytokines mediate the body's response to infection and inflammation. Long-term administration of tumor necrosis factor causes liver hypertrophy, and our laboratory has shown that tumor necrosis factor acutely increases hepatic DNA synthesis. The purpose of this study was to determine which specific cell types in the liver undergo DNA synthesis in response to tumor necrosis factor. Light microscopic autoradiographs of 3H-thymidine incorporation demonstrate that tumor necrosis factor stimulates DNA synthesis in nonparenchymal cells, whereas the low level of DNA synthesis normally found in hepatocytes remains unaffected. Tumor necrosis factor increased labeling in sinusoidal cells that appeared to be Kupffer cells and in cells localized to the portal tracts. With electron microscopy and histochemical staining for endogenous peroxidase, the sinusoidal cells were clearly identified as Kupffer cells. The exact identity of the cells in the portal tract is less certain, but some of the cells shared the characteristics of bile duct precursors. With long-term administration of tumor necrosis factor, a striking proliferation of bile ducts was seen. The functional role of the proliferation of bile ducts in response to tumor necrosis factor is unclear, and it is not known whether the increase is a beneficial or deleterious response. The increased DNA synthesis in Kupffer cells could result in a potentially beneficial response to infection by increasing an animal's ability to phagocytize and clear microorganisms. However, under some circumstances, an expansion of the number of Kupffer cells could be deleterious by increasing an animal's ability to produce tumor necrosis factor and other cytokines that in large quantities can have toxic effects.