Multifactorial regulation of hepcidin expression in hepatocytes. Hepcidin is regulated via multiple pathways. In inflammatory states, macrophages release interleukin-6 (IL-6), which activates the STAT3 pathway in hepatocytes, leading to production of hepcidin. Local iron stores induce nonhepatocyte liver cells to produce bone morphogenic protein 2 (BMP2) and BMP6, which stimulate BMP receptor I; this activates the s-mothers against decapentaplegic 1/5/8 (SMAD1/5/8) pathway, which in concert with SMAD4, translocates to the nucleus to induce hepcidin transcription. Increased systemic iron leads to presence of diferric transferrin compounds, which bind TfR1, disrupting its interaction with HFE, HFE complexing with TfR2, BMP receptor, or hemojuvelin (HJV), an iron-specific BMP coreceptor; this leads to potentiation of the BMP/SMAD1/5/8 signaling pathway and hepcidin transcription. BRE, TFIIB recognition element; LPS, lipopolysaccharide; SRE, serum response element.