Oncostatin M and leukemia inhibitory factor increase hepcidin expression in hepatoma cell lines
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Overproduction of hepcidin by interleukin-6 (IL-6) is considered to be the main factor responsible for the development of anemia in inflammatory conditions. Since oncostatin M (OSM), a member of the IL-6 family, plays an important role in immune and inflammatory responses, we assessed the effect of OSM on hepcidin expression, as well as that of leukemia inhibitory factor (LIF), another member of the IL-6 family. We found that hepcidin expression was markedly induced by OSM and LIF in a time- and dose-dependent manner in hepatoma cell lines, and this expression was induced independent of IL-6/IL-6 receptor signaling. Luciferase assay revealed that OSM and LIF stimulated a −1.3-kb hepcidin promoter. This effect was markedly reduced when the signal transducer and activator of transcription (STAT) site of the promoter was mutated, and was almost completely abolished in the presence of AG-490, a Janus kinase (JAK) inhibitor. Hence, the JAK/STAT pathway plays a major role in OSM- and LIF-induced activation of the hepcidin promoter. In conclusion, we demonstrated that OSM and LIF can induce hepcidin expression mainly through the JAK/STAT pathways. Further studies are warranted to evaluate the clinical significance of OSM and LIF in the development of anemia in various inflammatory diseases.
KeywordsOncostatin M Leukemia inhibitory factor Interleukin-6 Hepcidin
We thank Dr. Hideyuki Tsuchida (Division of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan) for measuring the hepcidin-25 levels in the cell culture supernatant. This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan; a grant from Takeda Science Foundation; and a grant for Project Research from the High-Technology Center of Kanazawa Medical University (H2007-2).
Conflict of interest statement
N.T. declares that he is also the President of Medical Care Proteomics Biotechnology Co. Ltd. (Ishikawa-ken, Japan), a start-up company, the stocks of which are not publicly traded. Other authors declare that they have no conflicts of interest relevant to this paper.
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