title: Friend of GATA and GATA-6 modulate the transcriptional up-regulation of hepcidin in hepatocytes during inflammation.
abstract: Hepcidin is an antimicrobial peptide hormone that plays a central role in the metabolism of iron and its expression in the liver can be induced through two major pathways: the inflammatory pathway, mainly via IL-6; and the iron-sensing pathway, mediated by BMP-6. GATA-proteins are group of evolutionary conserved transcriptional regulators that bind to the consensus motif-WGATAR-in the promoter region. In hepatoma cells, GATA-proteins 4 and 6 in conjunction with the co-factor friend of GATA (FOG) were shown to modulate the transcription of HAMP. However, it is unclear as to which of the GATA-proteins drive the expression of HAMP in vivo. In this study, using in vitro and in vivo approaches, we investigated the relevance of GATA and FOG proteins in the expression of hepcidin following treatment with IL-6 and BMP-6. We found that treatment of Huh7 cells with either IL-6 or BMP-6 increased the HAMP promoter activity. The HAMP promoter activity following treatment with IL-6 or BMP-6 was further increased by co-transfection of the promoter with GATA proteins 4 and 6. However, co-transfection of the HAMP promoter with FOG proteins 1 or 2 repressed the promoter response to treatments with either IL-6 or BMP-6. The effects of both GATA and FOG proteins on the promoter activity in response to IL-6 or BMP-6 treatment were abrogated by mutation of the GATA response element-TTATCT-in the HAMP promoter region -103/-98. In vivo, treatment of mice with lipopolysaccharide led to a transient increase of Gata-6 expression in the liver that was positively correlated with the expression of hepcidin. Our results indicate that during inflammation GATA-6 is up-regulated in concert with hepcidin while GATA-4 and FOG (1 and 2) are repressed.
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Institut du Cancer de Montréal, (ICM), University of Montreal, Pavillon De Sève Porte Y-5625, 2099 rue Alexandre De Sève, Montreal, QC, H2L 4M1, Canada, ebagu@yahoo.com.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Bagu
authors.forename: A
authors.initials: A
authors.lastname: Layoun
authors.forename: A
authors.initials: A
authors.lastname: Calvé
authors.forename: M M
authors.initials: MM
authors.lastname: Santos
mesh_terms: D000818:Animals; D001483:Base Sequence; D055418:Bone Morphogenetic Protein 6 / Q000494:pharmacology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D064451:Hepcidins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology; D008070:Lipopolysaccharides; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; C578702:HAMP protein, human; D064451:Hepcidins; C508600:IL6 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009687:Nuclear Proteins; D014157:Transcription Factors; C498432:ZFPM1 protein, human; C117427:ZFPM2 protein, human