title: The type I BMP receptor Alk3 is required for the induction of hepatic hepcidin gene expression by interleukin-6.
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.
authors: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine.
authors: Claire
authors: C
authors: Mayeur
authors: Lisa K
authors: LK
authors: Lohmeyer
authors: Patricio
authors: P
authors: Leyton
authors: Sonya M
authors: SM
authors: Kao
authors: Alexandra E
authors: AE
authors: Pappas
authors: Starsha A
authors: SA
authors: Kolodziej
authors: Ester
authors: E
authors: Spagnolli
authors: Binglan
authors: B
authors: Yu
authors: Rita L
authors: RL
authors: Galdos
authors: Paul B
authors: PB
authors: Yu
authors: Randall T
authors: RT
authors: Peterson
authors: Donald B
authors: DB
authors: Bloch
authors: Kenneth D
authors: KD
authors: Bloch
authors: Andrea U
authors: AU
authors: Steinbicker
mesh_terms: D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D064451:Hepcidins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D064451:Hepcidins; D015850:Interleukin-6; D007501:Iron; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I