Regulation of hepcidin transcription by interleukin-1 and interleukin-6.
Hepcidin is a peptide that regulates iron homeostasis by inhibiting iron absorption by the small intestine and release of iron from macrophages. Its production is stimulated by iron overload and by inflammation. It has been suggested that IL-6 is the only cytokine that stimulates hepcidin transcription. However, mice with targeted disruption of the gene encoding IL-6 (IL-6-/-) respond to endotoxin by increasing the expression of hepcidin transcripts in the liver. We show that incubating murine hepatocytes with IL-6, IL-1alpha, and IL-1beta strongly stimulates hepcidin transcription. IL-10 has little or no stimulatory effect, and IFN-beta inhibits transcription of hepcidin. All of the hepcidin stimulatory activity of macrophages from IL-6-/- mice can be accounted for by IL-1 that they secrete. Hepatocytes from IL-6-/- mice, hfe-/- mice, and mice with a hypomorphic transferrin receptor 2 mutation responded to IL-6 and IL-1 by up-regulating hepcidin transcription. Nitric oxide does not seem to be involved in the stimulation of hepcidin transcription by cytokines: aminoguanidine does not inhibit the stimulation of hepcidin transcription by cytokines. IL-1 may play a significant role in the anemia of inflammation by up-regulating hepcidin.
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
Wang
Lei
L
Beutler
Ernest
E
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D005786:Gene Expression Regulation; D006146:Guanidines / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D064451:Hepcidins; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology*; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D023181:Antimicrobial Cationic Peptides; D017077:Culture Media, Conditioned; D006146:Guanidines; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D007375:Interleukin-1; D015850:Interleukin-6; D011990:Receptors, Transferrin; C503640:TFR2 protein, human; C503641:TFR2 protein, mouse; D019001:Nitric Oxide Synthase; C004479:pimagedine