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Hepcidin production in response to iron is controlled by monocyte-derived humoral factors

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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.

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Acknowledgments

The authors would like to thank Dr. Philip Aisen for reviewing this manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Product Research Department, Kamakura Research Labs, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan

    Yusuke Sasaki, Yasushi Shimonaka, Hirotaka Kanada & Yoshiyuki Moriguchi

  2. Division of Gastroenterology and Hematology/Oncology Department of Medicine, Asahikawa Medical College, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan

    Katsuya Ikuta, Takaaki Hosoki & Yutaka Kohgo

  3. Department of Gastroenterology, Asahikawa Red Cross Hospital, 1-1-1-1 Akebono, Asahikawa, Hokkaido, 070-8530, Japan

    Takaaki Hosoki

  4. Department of Gastrointestinal Immunology and Regenerative Medicine, Asahikawa Medical College, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan

    Katsunori Sasaki

  5. Oncology Center, Asahikawa Medical College Hospital, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan

    Yoshihiro Torimoto

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  1. Yusuke Sasaki
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  2. Yasushi Shimonaka
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  9. Yutaka Kohgo
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Correspondence to Yusuke Sasaki.

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Sasaki, Y., Shimonaka, Y., Ikuta, K. et al. Hepcidin production in response to iron is controlled by monocyte-derived humoral factors. Int J Hematol 99, 12–20 (2014). https://doi.org/10.1007/s12185-013-1476-8

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  • DOI: https://doi.org/10.1007/s12185-013-1476-8

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