Hepcidin induction by pathogens and pathogen-derived molecules is strongly dependent on interleukin-6.
Hepcidin, the iron-regulatory hormone, is increased during infection or inflammation, causing hypoferremia. This response is thought to be a host defense mechanism that restricts iron availability to invading pathogens. It is not known if hepcidin is differentially induced by bacterial versus viral infections, whether the stimulation of pattern recognition receptors directly regulates hepcidin transcription, or which of the proposed signaling pathways are essential for hepcidin increase during infection. We analyzed hepcidin induction and its dependence on interleukin-6 (IL-6) in response to common bacterial or viral infections in mice or in response to a panel of pathogen-derived molecules (PAMPs) in mice and human primary hepatocytes. In wild-type (WT) mice, hepcidin mRNA was induced several hundred-fold both by a bacterial (Streptococcus pneumoniae) and a viral infection (influenza virus PR8) within 2 to 5 days. Treatment of mice and human primary hepatocytes with most Toll-like receptor ligands increased hepcidin mRNA within 6 h. Hepcidin induction by microbial stimuli was IL-6 dependent. IL-6 knockout mice failed to increase hepcidin in response to S. pneumoniae or influenza infection and had greatly diminished hepcidin response to PAMPs. In vitro, hepcidin induction by PAMPs in primary human hepatocytes was abolished by the addition of neutralizing IL-6 antibodies. Our results support the key role of IL-6 in hepcidin regulation in response to a variety of infectious and inflammatory stimuli.
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
Richard
R
Rodriguez
Chun-Ling
CL
Jung
Victoria
V
Gabayan
Jane C
JC
Deng
Tomas
T
Ganz
Elizabeta
E
Nemeth
Yonca
Y
Bulut
D000818:Animals; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000821:virology*; D064451:Hepcidins / Q000096:biosynthesis*; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009975:Orthomyxoviridae / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000276:immunology
D064451:Hepcidins; D015850:Interleukin-6; C577686:interleukin-6, mouse