title: Hepcidin production in response to iron is controlled by monocyte-derived humoral factors.
abstract: 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.
authors.affiliation: Product Research Department, Kamakura Research Labs, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan, sasaki.yusuke@chugai-pharm.co.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shimonaka
authors.forename: Katsuya
authors.initials: K
authors.lastname: Ikuta
authors.forename: Takaaki
authors.initials: T
authors.lastname: Hosoki
authors.forename: Katsunori
authors.initials: K
authors.lastname: Sasaki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Torimoto
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kanada
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Moriguchi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kohgo
mesh_terms: D000818:Animals; D002460:Cell Line; D018920:Coculture Techniques; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D005290:Ferric Compounds / Q000008:administration & dosage / Q000494:pharmacology; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid / Q000008:administration & dosage / Q000494:pharmacology; D056945:Hep G2 Cells; D064451:Hepcidins / Q000096:biosynthesis* / Q000097:blood; D006801:Humans; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D013154:Spleen / Q000166:cytology; D014168:Transferrin / Q000494:pharmacology
chemical_list: D016207:Cytokines; D005290:Ferric Compounds; D064451:Hepcidins; D014168:Transferrin; C110714:holotransferrin; D007501:Iron; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid