RRC ID 50060
Author Kanamori Y, Murakami M, Sugiyama M, Hashimoto O, Matsui T, Funaba M.
Title Interleukin-1β (IL-1β) transcriptionally activates hepcidin by inducing CCAAT enhancer-binding protein δ (C/EBPδ) expression in hepatocytes.
Journal J Biol Chem
Abstract 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-1β (IL-1β) efficiently increases hepcidin expression in human HepG2 liver-derived cells and primary mouse hepatocytes. The primary region responsible for IL-1β-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-1β induces the expression of C/EBPδ but neither C/EBPα nor C/EBPβ in hepatocytes, and C/EBPδ bound to the C/EBP-BS in an IL-1β-dependent manner. Lipopolysaccharide (LPS) induced the expression of IL-1β 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-1β production in Kupffer cells and hepatocytes; 2) IL-1β 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-1β pathway stimulation leads to excess production of hepcidin, which could be causative to anemia of inflammation.
Volume 292(24)
Pages 10275-10287
Published 2017-6-16
DOI 10.1074/jbc.M116.770974
PII S0021-9258(20)40828-2
PMID 28438835
PMC PMC5473230
MeSH Animals CCAAT-Enhancer-Binding Protein-delta / agonists* CCAAT-Enhancer-Binding Protein-delta / antagonists & inhibitors CCAAT-Enhancer-Binding Protein-delta / genetics CCAAT-Enhancer-Binding Protein-delta / metabolism Cells, Cultured Culture Media, Conditioned Hep G2 Cells Hepatocytes / cytology Hepatocytes / drug effects Hepatocytes / immunology Hepatocytes / metabolism* Hepcidins / agonists* Hepcidins / genetics Hepcidins / metabolism Humans Interleukin-1beta / genetics Interleukin-1beta / metabolism* Kupffer Cells / cytology Kupffer Cells / drug effects Kupffer Cells / immunology Kupffer Cells / metabolism Lipopolysaccharides / toxicity Macrophages / drug effects Macrophages / immunology Macrophages / metabolism Male Mice Mice, Inbred C57BL Mice, Inbred ICR Promoter Regions, Genetic* / drug effects RAW 264.7 Cells RNA Interference Rats, Sprague-Dawley Recombinant Proteins / metabolism Up-Regulation* / drug effects
IF 4.238
Times Cited 22
DNA material rHpcidin(-1861)-luc (RDB15720) mIL-6(-300_-79)-luc (RDB15721).