Oncostatin M is a potent inducer of hepcidin, the iron regulatory hormone.
Erythropoietic activity is known to affect iron homeostasis through regulation of the liver iron regulatory hormone hepcidin. To identify new factors secreted by the erythroblasts that could influence hepcidin synthesis, we set up a coculture model. HuH7 hepatoma cells cocultured with primary human erythroblasts or erythroleukemic UT7 cells presented a 20- to 35-fold increase of hepcidin gene expression. This induction was fully blunted in the presence of a neutralizing oncostatin M antibody, demonstrating that this cytokine, belonging to the IL-6 family of cytokines, was responsible for increased levels of hepcidin expression. We further demonstrated that recombinant oncostatin M induced a dramatic transcriptional increase of hepcidin in HuH7 cells through specific activation of the STAT pathway. Hepcidin induction by oncostatin M was also observed in hepatocytes in primary culture and is believed to be cell specific since no induction was found in isolated bone marrow cells, macrophagic, stromal, and lymphoma-derived cell lines, nor in erythroblasts. Finally, we show that oncostatin M administration in vivo increases hepcidin expression and leads to significantly decreased serum iron levels. This work identifies a new potent inducer of hepcidin expression in the liver and supports a role for modulators of oncostatin M signaling pathway in treating iron disorders.
Chung
Bomee
B
Université Paris Descartes, Centre National de la Recherche Scientifique (UMR 8104), Paris, France.
Verdier
Frédérique
F
Matak
Pavle
P
Deschemin
Jean-Christophe
JC
Mayeux
Patrick
P
Vaulont
Sophie
S
D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004900:Erythroblasts / Q000378:metabolism*; D064451:Hepcidins; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D053683:Oncostatin M / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000378:metabolism
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D015850:Interleukin-6; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D053683:Oncostatin M; D007501:Iron; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3