title: Regulation of hepcidin expression by inflammation-induced activin B.
abstract: Activin B is induced in response to inflammation in the liver and enhances hepcidin expression, but the source of activin B and the molecular mechanism underlying hepcidin induction are not clear yet. Lipopolysaccharide (LPS)-induced inflammation induced inhibin βB but not inhibin α or inhibin βA expression in the liver, implicating activin B induction. Immunoreactive inhibin βB was detected in endothelial cells and Kupffer cells in LPS-treated liver. Activin B, but not activin A or activin AB, directly increased hepcidin expression. Activin B induced phosphorylation and activation of Smad1/5/8, the BMP-regulated (BR)-Smads. The stimulation of hepcidin transcription by activin B was mediated by ALK2 and ActRIIA, receptors for the TGF-β family. Unexpectedly, activin B-induced hepcidin expression and BR-Smad phosphorylation were resistant to the effects of LDN-193189, an ALK2/3/6 inhibitor. ALK2 and ActRIIA complex formation in response to activin B may prevent the approach of LDN-193189 to ALK2 to inhibit its activity. Activin B also induced phosphorylation of Smad2/3, the TGF-β/activin-regulated (AR)-Smad, and increased expression of connective tissue growth factor, a gene related to liver fibrogenesis, through ALK4 and ActRIIA/B. Activin B-induced activation of the BR-Smad pathway was also detected in non-liver-derived cells. The present study reveals the broad signaling of activin B, which is induced in non-parenchymal cells in response to hepatic inflammation, in hepatocytes.
authors.affiliation: Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kanamori
authors.affiliation: Laboratory of Veterinary Anatomy, Kitasato University School of Veterinary Medicine, Towada 034-8628, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sugiyama
authors.affiliation: Laboratory of Experimental Animal Science, Kitasato University School of Veterinary Medicine, Towada 034-8628, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Hashimoto
authors.affiliation: Laboratory of Molecular Biology, Azabu University School of Veterinary Medicine, Sagamihara 252-5201, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Funaba
mesh_terms: D030301:Activin Receptors, Type II / Q000378:metabolism; D028341:Activins / Q000378:metabolism*; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D002417:Cattle; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D064451:Hepcidins / Q000096:biosynthesis*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D051785:Smad Proteins / Q000378:metabolism
chemical_list: C578703:Hamp protein, rat; D064451:Hepcidins; D008070:Lipopolysaccharides; D051785:Smad Proteins; C044147:activin B; D028341:Activins; D030301:Activin Receptors, Type II; C000610415:Acvr1 protein, rat; D052005:Bone Morphogenetic Protein Receptors, Type I