In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2

被引:111
作者
Maes, Ken [3 ]
Nemeth, Elizabeta [1 ,2 ]
Roodman, G. David [4 ]
Huston, Alissa [4 ]
Esteve, Flavia [4 ]
Freytes, Cesar [5 ]
Callander, Natalie [6 ]
Katodritou, Eirini [7 ]
Tussing-Humphreys, Lisa [8 ]
Rivera, Seth [1 ,2 ]
Vanderkerken, Karin [3 ]
Lichtenstein, Alan [9 ]
Ganz, Tomas [1 ,2 ]
机构
[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol, Los Angeles, CA 90095 USA
[3] Vrije Univ Brussel VUB, Dept Hematol & Immunol, Brussels, Belgium
[4] Univ Pittsburgh, Sch Med & Pittsburgh, VA Med Ctr, Pittsburgh, PA USA
[5] Univ Texas Hlth Sci Ctr San Antonio, Audie L Murphy Mem Vet Hosp, San Antonio, TX 78229 USA
[6] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Div Hematol, Madison, WI USA
[7] Theagen Canc Ctr, Dept Hematol, Thessaloniki, Greece
[8] USDA ARS, Baton Rouge, LA USA
[9] W Los Angeles VA Univ Calif Los Angeles Med Ctr, Los Angeles, CA USA
基金
美国国家卫生研究院;
关键词
EXPRESSION; IL-6; PROMOTER; RECEPTORS; BMP; INFLAMMATION; INDUCTION; CYTOKINES; ELEMENTS; LESSONS;
D O I
10.1182/blood-2010-03-274571
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. (Blood. 2010;116(18):3635-3644)
引用
收藏
页码:3635 / 3644
页数:10
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