In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2.
Hepcidin is the principal iron-regulatory hormone and a pathogenic factor in anemia of inflammation. Patients with multiple myeloma (MM) frequently present with anemia. We showed that MM patients had increased serum hepcidin, which inversely correlated with hemoglobin, suggesting that hepcidin contributes to MM-related anemia. Searching for hepcidin-inducing cytokines in MM, we quantified the stimulation of hepcidin promoter-luciferase activity in HuH7 cells by MM sera. MM sera activated the hepcidin promoter significantly more than did normal sera. We then examined the role of bone morphogenetic proteins (BMPs) and interleukin-6 (IL-6), the major transcriptional regulators of hepcidin. Mutations in both BMP-responsive elements abrogated the activation dramatically, while mutations in the IL-6-responsive signal transducer and activator of transcription 3-binding site (STAT3-BS) had only a minor effect. Cotreatment with anti-BMP-2/4 or noggin-Fc blocked the promoter induction with all MM sera, anti-IL-6 blocked it with a minority of sera, whereas anti-BMP-4, -6, or -9 antibodies had no effect. BMP-2-immunodepleted MM sera had decreased promoter stimulatory capacity, and BMP-2 concentrations in MM sera were significantly higher than in normal sera. Our results demonstrate that BMP-2 is a major mediator of the hepcidin stimulatory activity of MM sera.
Maes
Ken
K
Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
Nemeth
Elizabeta
E
Roodman
G David
GD
Huston
Alissa
A
Esteve
Flavia
F
Freytes
Cesar
C
Callander
Natalie
N
Katodritou
Eirini
E
Tussing-Humphreys
Lisa
L
Rivera
Seth
S
Vanderkerken
Karin
K
Lichtenstein
Alan
A
Ganz
Tomas
T
D000740:Anemia / Q000150:complications* / Q000276:immunology*; D023181:Antimicrobial Cationic Peptides / Q000097:blood* / Q000235:genetics / Q000276:immunology; D055396:Bone Morphogenetic Protein 2 / Q000097:blood / Q000276:immunology*; D019485:Bone Morphogenetic Proteins / Q000276:immunology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006454:Hemoglobins / Q000378:metabolism; D064451:Hepcidins; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D009101:Multiple Myeloma / Q000150:complications* / Q000276:immunology*; D009154:Mutation; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000235:genetics
D023181:Antimicrobial Cationic Peptides; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; C578702:HAMP protein, human; D006454:Hemoglobins; D064451:Hepcidins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor