SECRETION OF FERRITIN BY RAT HEPATOMA-CELLS AND ITS REGULATION BY INFLAMMATORY CYTOKINES AND IRON

The possibility that serum ferritin is a secreted protein and an acute phase reactant regulated by inflammatory hormones and iron was examin ed in a hepatic cell line that secretes plasma proteins. Differentiate d rat hepatoma cells released albumin and ferritin into the medium, as determined by rocket immunoelectrophoresis and isolation of ferritin by standard procedures plus immunoaffinity chromatography, following l abeling with radioactive amino acid. Administration of interleukin-1-b eta (IL-1) or tumor necrosis factor-alpha (TNF) doubled the amounts of ferritin released into the medium over 24 and 48 hours. Together, the cytokines had more than an additive effect. Albumin secretion was dim inished by IL-1, but not TNF. Iron, administered as an iron dextran co mplex or as a 1:1. chelate with nitrilotriacetate (Fe-NTA), also enhan ced ferritin release, but had no effect on albumin. Intracellular ferr itin concentrations did not change significantly with cytokine treatme nt, but increased in response to iron. With or without treatments, rel ease of ferritin and albumin from cells into the medium was inhibited by brefeldin A, an inhibitor of Golgi function, The effect of each of the cytokines and of iron on ferritin and albumin was also blocked by dichlorofuranosylbenzimidazole (DRB), an inhibitor of transcription. T he stimulatory effect of Fe-NTA on ferritin secretion was diminished b y TNF, and this was partially counteracted by IL-1, indicating additio nal regulatory complexity. These results show for the first time that hepatic cells secrete ferritin, that this ferritin secretion is regula ted by iron and inflammatory cytokines, and that the mechanisms of reg ulation differ from those for intracellular ferritin. The results woul d explain why serum ferritin increases in inflammation or when iron fl ux is enhanced. (C) 1997 by The American Society of Hematology.