The antimicrobial peptide hepcidin appears to play a central role in the regulation of iron homeostasis. In intact animals, iron overload or the injection of lipopolysaccharide (LPS) stimulates transcription of HAMP , the gene that encodes hepcidin. In isolated hepatocytes, IL-6, an inflammatory cytokine the production of which is stimulated by LPS, up-regulates transcription of hepcidin. In contrast, iron has no stimulatory effect on hepcidin expression in isolated hepatocytes. There is apparently a signaling pathway, activated by iron, that is present in the intact animal but not in isolated hepatocytes. Studies in humans and mice have shown that this iron-dependent pathway requires the presence of Hfe, hemojuvelin, and probably transferrin receptor 2 (tfr-2). To determine whether activation of hepcidin transcription by IL-6 also requires Hfe and tfr-2, we have studied mice homozygous for targeted disruption of HFE , β 2 -microglobulin, and for a truncating mutation of TFR-2 . We show that these mutant mice react normally to injection of endotoxin and that their isolated hepatocytes react normally to IL-6. This indicates that the signaling pathway activated by IL-6 does not require either Hfe or tfr-2. Mice with disruption of the gene encoding IL-6 seem to have a blunted response to LPS, but the statistical significance of the small response documented is borderline. It is therefore not clear whether LPS stimulates secretion of cytokines other than IL-6 that may stimulate hepcidin transcription.

Lee, P., Peng, H., Gelbart, T., & Beutler, E. (2004). The IL-6- and lipopolysaccharide-induced transcription of hepcidin in HFE- , transferrin receptor 2-, and β 2 -microglobulin-deficient hepatocytes. Proceedings of the National Academy of Sciences, 101(25), 9263–9265.