Regulation of iron metabolism in HepG2 cells: A possible role for cytokines in the hepatic deposition of iron

Abstract

In chronic inflammation it is reported that serum iron is depleted and hepatic iron is increased because of reticuloendothelial system iron blockade. However, recent studies indicate that hepatic parenchymal cells increase the uptake of transferrin-bound iron after in vivo stimulation with bacterial lipopolysaccharide, suggesting that endotoxemia itself or lipopolysaccharide-induced production of inflammation-related cytokines may also be responsible for this phenomenon. In this study the actions of inflammation-related cytokines on the synthesis of iron-binding proteins (transferrin and ferritin) and transferrin receptor and the uptake of transferrin-bound iron were investigated in a human hepatoblastoma cell line, HepG2, which is the most commonly used cell line for examining the regulation of hepatic protein synthesis by cytokines. The cells were exposed to interleukin-1 beta, interleukin-6 or tumor necrosis factor-alpha separately for 24 hr. In each cytokine treatment group, the level of transferrin, which is secreted into the conditioned medium, was found to be decreased compared with that of untreated cells. On the other hand, the biosynthesis of ferritin was markedly elevated after the same treatment. This increase in ferritin by cytokine treatment was diminished when deferoxamine was used concomitantly to deplete intracellular chelatable iron. After stimulation with interleukin-1 beta, interleukin-6 or tumor necrosis factor-alpha, 59Fe-labeled transferrin uptake into the cells was increased by 36%, 48%, or 18%, respectively, and this uptake was inhibited by the addition of excess unlabeled transferrin. A binding study with 125I-labeled diferric transferrin revealed that the three cytokines increased the number of transferrin receptors on the cell surface by 1.15-fold to 1.35-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor necrosis factor α promoter polymorphisms influence the phenotypic expression of hereditary hemochromatosis

“…This cytokine modulates expression of H and L ferritin and of the transferrin receptor in different cell types, including monocytes, 33 hepatocytes, 34,35 and duodenocytes, 36 as well as of HFE protein. 36 A relation between TNF-␣ and HHC was first suggested after it was observed that stimulated monocytes from patients with HHC released a lower amount of TNF-␣ than did monocytes from controls.…”

Nitric Oxide Reduces Nontransferrin–Bound Iron Transport in Hepg2 Cells

“…Increased iron deposition in the liver after the induction of inflammation has been reported, [49][50][51] and this has been partially attributed to NO production. 13,14 However, the role of NO in iron homeostasis is complex and involves different pathways, [11][12][13][14]18,19 including NTBI uptake.…”

Targeting the interleukin‐6 receptor: A new treatment for systemic juvenile idiopathic arthritis?

“…In contrast, IL-6 stimulates both hypoxia-induced erythropoietin production (35) and erythroid progenitor proliferation (36). Furthermore, it increases ferritin expression and hepatic uptake of serum iron (37,38), resulting in reticuloendothelial iron block. Moreover, some patients with systemic JIA and long-lasting severe anemia develop iron malabsorption (39).…”