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.