Different regulatory elements are required for response of hepcidin to interleukin-6 and bone morphogenetic proteins 4 and 9.
Hepcidin is a major regulator of iron homeostasis. Hepcidin expression is upregulated by inflammatory cytokines, particularly interleukin (IL)-6 and even more potently by the bone morphogenetic proteins 2, 4 and 9 (BMP-2, BMP-4 and BMP-9). This study showed that the regulation of hepcidin expression by IL-6 and BMPs occurs through distinct regulatory elements. The induction of hepcidin by BMPs requires at least two regions of the Hamp1 promoter, one between 140-260 bp and the other between 1.6-2.0 kb upstream of the start of translation. Reporter constructs including 1.6-2.0 kb of the Hamp1 promoter were induced >16-fold by BMPs whereas a 260 bp reporter Hamp1 promoter construct was induced only two- to threefold. The distal 1.6-2.0 kb region appeared to contain several different BMP-responsive elements, as incremental lengthening of the promoter construct in this region produced gradual escalation of BMP-responsiveness. In contrast, the IL-6 response required only the proximal 260 bp Hamp1 promoter region. Furthermore, there were no regulatory elements located in the non-coding or coding regions of Hamp1 and activation of the Hamp1 promoter was absent or markedly reduced in cells of non-hepatic origin.
Truksa
Jaroslav
J
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Peng
Hongfan
H
Lee
Pauline
P
Beutler
Ernest
E
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002460:Cell Line; D003001:Cloning, Molecular; D005786:Gene Expression Regulation / Q000187:drug effects*; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D064451:Hepcidins; D006706:Homeostasis; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D016415:Sequence Alignment; D013268:Stimulation, Chemical; D014158:Transcription, Genetic
D023181:Antimicrobial Cationic Peptides; C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C525887:GDF2 protein, human; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D015850:Interleukin-6; D007501:Iron