Involvement of hepcidin in the anemia of multiple myeloma.
OBJECTIVE
Hepcidin is a liver-produced peptide implicated in the anemia of inflammation. Because interleukin (IL)-6 is a potent inducer of hepcidin expression and its levels are elevated in multiple myeloma, we studied the role of hepcidin in the anemia of multiple myeloma.


METHODS
Urinary hepcidin and serum levels of IL-6, ferritin, C-reactive protein, tumor necrosis factor-alpha, and IL-1 beta were studied in newly diagnosed myeloma patients. In vitro hepcidin induction assay was assessed by real-time PCR assay.


RESULTS
Pretreatment urinary hepcidin levels in 44 patients with stage III multiple myeloma were 3-fold greater than normal controls. In the subset of multiple myeloma patients without renal insufficiency (n = 27), a marked inverse correlation was seen between hemoglobin at diagnosis and urinary hepcidin level (P = 0.014) strongly supporting a causal relationship between up-regulated hepcidin expression and anemia. The urinary hepcidin also significantly (P < 0.05) correlated with serum ferritin and C-reactive protein, whereas its correlation with serum IL-6 levels was of borderline significance (P = 0.06). Sera from 14 multiple myeloma patients, with known elevated urinary hepcidin, significantly induced hepcidin mRNA in the Hep3B cells, whereas normal sera had no effect. For 10 patients, the ability of anti-IL-6 and anti-IL-6 receptor antibodies to prevent the serum-induced hepcidin RNA was tested. In 6 of these patients, hepcidin induction was abrogated by the anti-IL-6 antibodies, but in the other 4 patients, the neutralizing antibodies had no effect.


CONCLUSIONS
These results indicate hepcidin is up-regulated in multiple myeloma patients by both IL-6-dependent and IL-6-independent mechanisms and may play a role in the anemia of multiple myeloma.
Sharma
Sanjai
S
West Los Angeles VA-University of California-Los Angeles Medical Center, Los Angeles, CA 90073, USA. sasharma@mednet.ucla.edu
Nemeth
Elizabeta
E
Chen
Yi-Hsiang
YH
Goodnough
Julia
J
Huston
Alissa
A
Roodman
G D
GD
Ganz
Tomas
T
Lichtenstein
Alan
A
D000740:Anemia / Q000150:complications*; D023181:Antimicrobial Cationic Peptides / Q000652:urine*; D002097:C-Reactive Protein / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005293:Ferritins / Q000097:blood; D064451:Hepcidins; D006801:Humans; D007249:Inflammation / Q000150:complications*; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D009101:Multiple Myeloma / Q000150:complications*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D015854:Up-Regulation
D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; D064451:Hepcidins; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D005293:Ferritins