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Interleukin-1ß (IL-1ß) transcriptionally activates hepcidin by inducing CCAAT enhancer-binding protein δ (C/EBPδ) expression in hepatocytes.
Kanamori, Yohei; Murakami, Masaru; Sugiyama, Makoto; Hashimoto, Osamu; Matsui, Tohru; Funaba, Masayuki.
Afiliación
  • Kanamori Y; From the Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502.
  • Murakami M; the Laboratory of Molecular Biology, Azabu University School of Veterinary Medicine, Sagamihara 252-5201, and.
  • Sugiyama M; the Laboratory of Veterinary Anatomy and.
  • Hashimoto O; Laboratory of Experimental Animal Science, Kitasato University School of Veterinary Medicine, Towada 034-8628, Japan.
  • Matsui T; From the Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502.
  • Funaba M; From the Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, mfunaba@kais.kyoto-u.ac.jp.
J Biol Chem ; 292(24): 10275-10287, 2017 06 16.
Article en En | MEDLINE | ID: mdl-28438835
Hepcidin is a liver-derived hormone that negatively regulates serum iron levels and is mainly regulated at the transcriptional level. Previous studies have clarified that in addition to hepatic iron levels, inflammation also efficiently increases hepatic hepcidin expression. The principle regions responsible for efficient hepcidin transcription are bone morphogenetic protein-responsive elements (BMP-REs) 1 and 2 as well as the signal transducer and activator of transcription 3-binding site (STAT-BS). Here, we show that the proinflammatory cytokine interleukin-1ß (IL-1ß) efficiently increases hepcidin expression in human HepG2 liver-derived cells and primary mouse hepatocytes. The primary region responsible for IL-1ß-mediated hepcidin transcription was the putative CCAAT enhancer-binding protein (C/EBP)-binding site (C/EBP-BS) at the hepcidin promoter spanning nucleotides -329 to -320. IL-1ß induces the expression of C/EBPδ but neither C/EBPα nor C/EBPß in hepatocytes, and C/EBPδ bound to the C/EBP-BS in an IL-1ß-dependent manner. Lipopolysaccharide (LPS) induced the expression of IL-1ß in Kupffer cells and hepatocytes in the mouse liver; furthermore, the culture supernatants from the macrophage-like cell line RAW264.7 treated with LPS potentiated the stimulation of hepcidin expression in hepatocytes. The present study reveals that: 1) inflammation induces IL-1ß production in Kupffer cells and hepatocytes; 2) IL-1ß increases C/EBPδ expression in hepatocytes; and 3) induction of C/EBPδ activates hepcidin transcription via the C/EBP-BS that has been uncharacterized yet. In cooperation with the other pathways activated by inflammation, IL-1ß pathway stimulation leads to excess production of hepcidin, which could be causative to anemia of inflammation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación hacia Arriba / Regiones Promotoras Genéticas / Hepatocitos / Proteína delta de Unión al Potenciador CCAAT / Interleucina-1beta / Hepcidinas Idioma: En Revista: J Biol Chem Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación hacia Arriba / Regiones Promotoras Genéticas / Hepatocitos / Proteína delta de Unión al Potenciador CCAAT / Interleucina-1beta / Hepcidinas Idioma: En Revista: J Biol Chem Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos