Different regulatory elements are required for response of hepcidin to interleukin‐6 and bone morphogenetic proteins 4 and 9

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Summary: 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.

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