REGULATION OF TUMOR NECROSIS FACTOR-ALPHA-MESSENGER-RNA SYNTHESIS ANDDISTRIBUTION OF TUMOR NECROSIS FACTOR-ALPHA-MESSENGER-RNA SYNTHESIZING CELLS IN RAT-LIVER DURING EXPERIMENTAL ENDOTOXEMIA

Stimulated liver macrophages (Kupffer cells) are known to release a va riety of inflammation-related substances, e.g. cytokines, prostanoids, and reactive oxygen intermediates. For instance, exposure of Kupffer cells in vitro to lipopolysaccharide (endotoxin) leads to a strongly e nhanced synthesis of the mRNA for tumor necrosis factor-alpha, the rel ease of the mature protein into culture media. These events are influe nced by prostanoids and corticoid hormones. Kupffer cells are thought to be the only source of tumor necrosis factor-alpha within the hepati c sinusoid, but neither this cell specificity nor the regulatory influ ence of glucocorticoids or prostanoids has been confirmed in the intac t organ. Using non-radioactive in situ hybridization, it was possible to obtain specific signals for tumor necrosis factor-alpha-mRNA in ind ividual Kupffer cells uniformly distributed (as compared to Kupffer ce lls detected by immunohistochemistry) throughout the liver. Kupffer ce lls were the only cells in the hepatic sinusoids of lipopolysaccharide -perfused livers to express mRNA for tumor necrosis factor-alpha. Simu ltaneous addition of endotoxin plus dexamethasone and endotoxin and pr ostaglandin E(2) compzletely suppressed the synthesis of this mRNA. Un expectedly, the presence of mRNA for tumor necrosis factor-alpha was a lso detected in the intrahepatic bile duct epithelium of lipopolysacch aride-perfused livers. It is known that biologically active endotoxin is secreted via the bile ducts. These results seem to indicate that bi le duct epithelium responds to inflammatory agents with synthesis of t umor necrosis factor-alpha-mRNA. One must also consider new functional aspects of bile duct epithelium in chronic inflammatory diseases, e.g . primary biliary cirrhosis, chronic sclerosing cholangitis or graft-v ersus-host disease. (C) Journal of Hepatology.