The IL-6- and lipopolysaccharide-induced transcription of hepcidin in HFE-, transferrin receptor 2-, and beta 2-microglobulin-deficient hepatocytes.
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, beta(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
Pauline
P
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Peng
Hongfan
H
Gelbart
Terri
T
Beutler
Ernest
E
D000818:Animals; D002478:Cells, Cultured; D017931:DNA Primers; D000071020:Hemochromatosis Protein; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000502:physiology*; D015850:Interleukin-6 / Q000494:pharmacology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction / Q000379:methods; D011990:Receptors, Transferrin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics*; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011990:Receptors, Transferrin; C503640:TFR2 protein, human; C503641:TFR2 protein, mouse; D001613:beta 2-Microglobulin