title: Activin B Induces Noncanonical SMAD1/5/8 Signaling via BMP Type I Receptors in Hepatocytes: Evidence for a Role in Hepcidin Induction by Inflammation in Male Mice.
abstract: Induction of the iron regulatory hormone hepcidin contributes to the anemia of inflammation. Bone morphogenetic protein 6 (BMP6) signaling is a central regulator of hepcidin expression in the liver. Recently, the TGF-β/BMP superfamily member activin B was implicated in hepcidin induction by inflammation via noncanonical SMAD1/5/8 signaling, but its mechanism of action and functional significance in vivo remain uncertain. Here, we show that low concentrations of activin B, but not activin A, stimulate prolonged SMAD1/5/8 signaling and hepcidin expression in liver cells to a similar degree as canonical SMAD2/3 signaling, and with similar or modestly reduced potency compared with BMP6. Activin B stimulates hepcidin via classical activin type II receptors ACVR2A and ACVR2B, noncanonical BMP type I receptors activin receptor-like kinase 2 and activin receptor-like kinase 3, and SMAD5. The coreceptor hemojuvelin binds to activin B and facilitates activin B-SMAD1/5/8 signaling. Activin B-SMAD1/5/8 signaling has some selectivity for hepatocyte-derived cells and is not enabled by hemojuvelin in other cell types. Liver activin B mRNA expression is up-regulated in multiple mouse models of inflammation associated with increased hepcidin and hypoferremia, including lipopolysaccharide, turpentine, and heat-killed Brucella abortus models. Finally, the activin inhibitor follistatin-315 blunts hepcidin induction by lipopolysaccharide or B. abortus in mice. Our data elucidate a novel mechanism for noncanonical SMAD activation and support a likely functional role for activin B in hepcidin stimulation during inflammation in vivo.
authors.affiliation: Program in Anemia Signaling Research (S.C., A.B.C., K.B.Z.-B., M.M., C.-Y.W., J.L.B.), Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Center for Hemochromatosis (S.C., A.P.), University Hospital of Modena and Reggio Emilia, Modena Italy 41124; and Department of Veterinary and Animal Science (A.S.), University of Massachusetts Amherst, Amherst, Massachusetts 01003.
authors.forename: Susanna
authors.initials: S
authors.lastname: Canali
authors.affiliation: Program in Anemia Signaling Research (S.C., A.B.C., K.B.Z.-B., M.M., C.-Y.W., J.L.B.), Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Center for Hemochromatosis (S.C., A.P.), University Hospital of Modena and Reggio Emilia, Modena Italy 41124; and Department of Veterinary and Animal Science (A.S.), University of Massachusetts Amherst, Amherst, Massachusetts 01003.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Core
authors.affiliation: Program in Anemia Signaling Research (S.C., A.B.C., K.B.Z.-B., M.M., C.-Y.W., J.L.B.), Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Center for Hemochromatosis (S.C., A.P.), University Hospital of Modena and Reggio Emilia, Modena Italy 41124; and Department of Veterinary and Animal Science (A.S.), University of Massachusetts Amherst, Amherst, Massachusetts 01003.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Zumbrennen-Bullough
authors.affiliation: Program in Anemia Signaling Research (S.C., A.B.C., K.B.Z.-B., M.M., C.-Y.W., J.L.B.), Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Center for Hemochromatosis (S.C., A.P.), University Hospital of Modena and Reggio Emilia, Modena Italy 41124; and Department of Veterinary and Animal Science (A.S.), University of Massachusetts Amherst, Amherst, Massachusetts 01003.
authors.forename: Maria
authors.initials: M
authors.lastname: Merkulova
authors.affiliation: Program in Anemia Signaling Research (S.C., A.B.C., K.B.Z.-B., M.M., C.-Y.W., J.L.B.), Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Center for Hemochromatosis (S.C., A.P.), University Hospital of Modena and Reggio Emilia, Modena Italy 41124; and Department of Veterinary and Animal Science (A.S.), University of Massachusetts Amherst, Amherst, Massachusetts 01003.
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Program in Anemia Signaling Research (S.C., A.B.C., K.B.Z.-B., M.M., C.-Y.W., J.L.B.), Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Center for Hemochromatosis (S.C., A.P.), University Hospital of Modena and Reggio Emilia, Modena Italy 41124; and Department of Veterinary and Animal Science (A.S.), University of Massachusetts Amherst, Amherst, Massachusetts 01003.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Schneyer
authors.affiliation: Program in Anemia Signaling Research (S.C., A.B.C., K.B.Z.-B., M.M., C.-Y.W., J.L.B.), Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Center for Hemochromatosis (S.C., A.P.), University Hospital of Modena and Reggio Emilia, Modena Italy 41124; and Department of Veterinary and Animal Science (A.S.), University of Massachusetts Amherst, Amherst, Massachusetts 01003.
authors.forename: Antonello
authors.initials: A
authors.lastname: Pietrangelo
authors.affiliation: Program in Anemia Signaling Research (S.C., A.B.C., K.B.Z.-B., M.M., C.-Y.W., J.L.B.), Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Center for Hemochromatosis (S.C., A.P.), University Hospital of Modena and Reggio Emilia, Modena Italy 41124; and Department of Veterinary and Animal Science (A.S.), University of Massachusetts Amherst, Amherst, Massachusetts 01003.
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Babitt
mesh_terms: D028341:Activins / Q000494:pharmacology*; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D064451:Hepcidins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation; D008297:Male; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051898:Smad1 Protein / Q000187:drug effects / Q000378:metabolism; D051902:Smad5 Protein / Q000187:drug effects / Q000378:metabolism; D051904:Smad8 Protein / Q000187:drug effects / Q000378:metabolism; D020349:Surface Plasmon Resonance
chemical_list: D064451:Hepcidins; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; C422405:activin A; C044147:activin B; D028341:Activins; D052005:Bone Morphogenetic Protein Receptors, Type I