Secretion of Ferritin by Rat Hepatoma Cells and Its Regulation by Inflammatory Cytokines and Iron

Abstract

The possibility that serum ferritin is a secreted protein and an acute phase reactant regulated by inflammatory hormones and iron was examined in a hepatic cell line that secretes plasma proteins. Differentiated 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 labeling with radioactive amino acid. Administration of interleukin-1–β (IL-1) or tumor necrosis factor-α (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 diminished by IL-1, but not TNF. Iron, administered as an iron dextran complex or as a 1:1 chelate with nitrilotriacetate (Fe-NTA), also enhanced ferritin release, but had no effect on albumin. Intracellular ferritin concentrations did not change significantly with cytokine treatment, but increased in response to iron. With or without treatments, release 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. The stimulatory effect of Fe-NTA on ferritin secretion was diminished by TNF, and this was partially counteracted by IL-1, indicating additional regulatory complexity. These results show for the first time that hepatic cells secrete ferritin, that this ferritin secretion is regulated by iron and inflammatory cytokines, and that the mechanisms of regulation differ from those for intracellular ferritin. The results would explain why serum ferritin increases in inflammation or when iron flux is enhanced.

Cytokine Release Syndrome in COVID-19 Patients, A New Scenario for an Old Concern: The Fragile Balance between Infections and Autoimmunity

“…In particular, it has been hypothesized that during an ongoing infection, the signaling mediated by bacterial/viral CpG DNA and TLR9 could activate the inflammasome, leading to IL-1 and IL-18 production [18][19][20]. Through DAMP signaling, infection could also increase the production of hemoglobin [21] and activate macrophages, which are prominent producers of ferritin [22,23], amplifying the inflammatory loop [23]. Moreover, a correlation between the serum levels of CD163, a marker of macrophage activation [24], and ferritin in patients with MAS has been reported [25].…”

Unexplained isolated hyperferritinemia without iron overload

“…Small amount of ferritin are present in the blood and consist of ferritin L, a glycosylated form of L termed ferritin G, and trace amounts of ferritin H . It is mainly secreted from macrophages, by hepatocytes, and lymphoid cells, but most aspects of its secretion remain unknown. Serum ferritin has a wide clinical utility primarily as an indicator of intracellular iron stores .…”

Ferroportin1 in hepatocytes and macrophages is required for the efficient mobilization of body iron stores in mice

“…These data suggest that the role of Fpn1 in hepatocytes might not be as important as it is in duodenal enterocytes or macrophages. Moreover, several studies have shown that hepatocytes can secrete the iron storage protein, ferritin, a process that can be enhanced by iron stimulation 22, 23. Hepatocytes also express high levels of the heme transporter, feline leukemia virus subgroup C receptor 24.…”