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.

Identification of a 250 kDa putative microtubule‐associated protein as bovine ferritin

“…Although some differences were detected between the serum ferritin and the intracellular ferritin, the serum ferritin was shown to be tissue-derived through secretion. Under normal circumstances, equilibrium is maintained between intracellular and extracellular ferritin, but the concentration of ferritin in serum and other biological fluids may rise, depending on the iron status of the body, and under various physiological circumstances [17][18][19]. In a couple of studies, Ramm et al [20,21] showed that the administration of the microtubule depolymerizing drugs colchicine and vinblastine, in normal and iron-loaded rats, inhibited ferritin uptake and significantly increased the release of endogenous ferritin in both the serum and bile, suggesting that disturbed microtubule function could account for these results.…”

Single‐Dose Pharmacokinetics of Sodium Ferric Gluconate Complex in Iron‐Deficient Subjects

“…Two published studies have shown that serum ferritin is a protein secreted in response to exposure of cells to exogenous iron; it is distinct from intracellular ferritin. 27,28 Thus, this rise in serum ferritin can not be accounted for by release of ferritin from stores in tissue.…”

β‐Aminoisobutyric Acid Prevents Diet‐induced Obesity in Mice With Partial Leptin Deficiency

“…Serum levels of ferritin can be increased in nonalcoholic fatty liver diseases, with higher levels in nonalcoholic steatohepatitis compared to simple steatosis (46,47). Increased ferritin could be independent of iron stores, and data suggest that it could be secondary to inflammation (47,48). Hence, reduction of ferritin levels in ob/+ mice treated with BAIBA could reflect lower necroinflammation ( Table 7).…”