1. The type I BMP receptor Alk3 is required for the induction of hepatic hepcidin gene expression by interleukin-6.
- Author
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Mayeur C, Lohmeyer LK, Leyton P, Kao SM, Pappas AE, Kolodziej SA, Spagnolli E, Yu B, Galdos RL, Yu PB, Peterson RT, Bloch DB, Bloch KD, and Steinbicker AU
- Subjects
- Animals, Bone Morphogenetic Protein Receptors, Type I genetics, Hep G2 Cells, Hepcidins metabolism, Humans, Iron metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Bone Morphogenetic Protein Receptors, Type I physiology, Gene Expression Regulation, Hepcidins genetics, Interleukin-6 pharmacology, Liver drug effects, Liver metabolism
- Abstract
Increased IL-6 production induces, via STAT3 phosphorylation, hepatic transcription of the gene encoding the iron-regulatory hormone, hepcidin, leading to development of anemia of chronic disease (ACD). Inhibition of bone morphogenetic protein (BMP) signaling prevents the induction of hepcidin gene expression by IL-6 and ameliorates ACD. Using mice with hepatocyte-specific deficiency of Alk2 or Alk3, we sought to identify the BMP type I receptor that participates in IL-6-mediated induction of hepcidin gene expression. Mice were injected with adenovirus specifying IL-6 (Ad.IL-6) or control adenovirus. Seventy-two hours later, serum iron concentrations and hepatic levels of STAT3 phosphorylation and hepcidin messenger RNA were measured. Additional mice were injected with recombinant murine IL-6 (mIL-6) or vehicle, and hepatic hepcidin gene expression was measured 4 hours later. Deficiency of Alk2 or Alk3 did not alter the ability of Ad.IL-6 injection to induce hepatic STAT3 phosphorylation. Ad.IL-6 increased hepatic hepcidin messenger RNA levels and decreased serum iron concentrations in Alk2- but not Alk3-deficient mice. Similarly, administration of mIL-6 induced hepatic hepcidin gene expression in Alk2- but not Alk3-deficient mice. These results demonstrate that the ability of IL-6 to induce hepatic hepcidin gene expression and reduce serum iron concentrations is dependent on the BMP type I receptor Alk3.
- Published
- 2014
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