A hypothetical scheme of activation of the murine Hamp1 promoter. Fully active promoter complex requires the presence of both the SMAD1/4 complexes as well as STAT3. Elements depicted as critical reduce/impair the ability of the promoter to respond to such stimuli. Our data suggest that the proximal STAT site is crucial for IL-6 responsiveness, and there seems to be another weaker as yet unidentified modulatory site between proximal 140 and 260 bp (question mark). On the other hand, proximal BMP-RE1, unidentified proximal modulatory site between 140 and 260 bp (question mark) and distal BMP-RE2/bZIP/HNF4/COUP are critical for the BMP/SMAD1/HJV pathway. The absence of any critical responsive element leads to a decrease in basal expression of hepcidin promoter, thereby, affecting the total response of the promoter to all stimuli even if the actual ability to respond is not compromised. The assembly of multiple transcription factors in an activation complex would explain the crosstalk between the inflammatory pathway and BMP/SMAD1/HJV pathway even though the actual responsive elements are quite distinct. Furthermore, our data suggest that there are additional accessory proteins that facilitate formation of a fully active promoter complex by binding to the region flanking the BMPRE2/bZIP/HNF4α/COUP motifs. The scheme for the human HAMP promoter would be similar and require the distal −2.3 to −2.5 kb region.