Hepcidin, which is mainly produced by the liver, is the key regulator in
iron homeostasis.
Hepcidin expression is up-regulated by
iron loading in vivo, but the mechanism underlying this process is not completely understood. In the present study, we investigated the mechanism, following the hypothesis that
hepcidin production in response to
iron loading is regulated by extra-hepatic
iron sensors. We measured serum
hepcidin concentrations and
iron indices in Wistar rats treated with
saccharated ferric oxide (SFO). Human
hepatoma-derived HepG2 cells were stimulated using SFO-administered rat sera, and co-cultured with rat spleen cells, human monocyte-derived THP-1 cells, or human monocytes with
diferric transferrin (holo-Tf), and
hepcidin concentrations in the
conditioned media were measured. SFO elevated rat serum
hepcidin concentrations. SFO-treated rat sera increased
hepcidin production from HepG2 cells, and this induction correlated with serum
hepcidin levels, but not with
iron indices. Holo-Tf up-regulated
hepcidin concentrations in media from HepG2 cells co-cultured with rat spleen cells, THP-1 cells, or human monocytes with or without cell-to-cell contacts, while holo-Tf did not up-regulate
hepcidin from HepG2 cells alone. Our results suggest the existence of humoral factors capable of inducing
hepcidin production that are secreted by extra-hepatic cells, such as reticuloendothelial monocytes, in response to
iron.