1. Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation.
- Author
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Steinbicker AU, Sachidanandan C, Vonner AJ, Yusuf RZ, Deng DY, Lai CS, Rauwerdink KM, Winn JC, Saez B, Cook CM, Szekely BA, Roy CN, Seehra JS, Cuny GD, Scadden DT, Peterson RT, Bloch KD, and Yu PB
- Subjects
- Animals, Antimicrobial Cationic Peptides metabolism, Bone Morphogenetic Protein Receptors, Type I antagonists & inhibitors, Carrier Proteins pharmacology, Hematopoietic Stem Cells drug effects, Hep G2 Cells, Hepcidins, Humans, Interleukin-6 pharmacology, Mice, Mice, Inbred C57BL, Pyrazoles pharmacology, Pyrimidines pharmacology, Recombinant Proteins pharmacology, Signal Transduction drug effects, Turpentine toxicity, Zebrafish, Zebrafish Proteins metabolism, Anemia etiology, Anemia prevention & control, Bone Morphogenetic Proteins antagonists & inhibitors, Inflammation complications
- Abstract
Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6-induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects that were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation.
- Published
- 2011
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