title: Hepcidin regulation by innate immune and infectious stimuli.
abstract: Hepcidin controls the levels and distribution of iron, an element whose availability can influence the outcome of infections. We investigated hepcidin regulation by infection-associated cytokines, pathogen-derived molecules, and whole pathogens in vitro and in vivo. We found that IL-22, an effector cytokine implicated in responses to extracellular infections, caused IL-6-independent hepcidin up-regulation in human hepatoma cells, suggesting it might represent an additional inflammatory hepcidin agonist. Like IL-6, IL-22 caused phosphorylation of STAT3 and synergized with BMP6 potentiating hepcidin induction. In human leukocytes, IL-6 caused potent, transient hepcidin up-regulation that was augmented by TGF-β1. Pathogen-derived TLR agonists also stimulated hepcidin, most notably the TLR5 agonist flagellin in an IL-6-dependent manner. In contrast, leukocyte hepcidin induction by heat-killed Candida albicans hyphae was IL-6-independent, but partially TGF-β-dependent. In a murine acute systemic candidiasis model, C albicans strongly stimulated hepcidin, accompanied by a major reduction in transferrin saturation. Similarly, hepcidin was up-regulated with concomitant lowering of serum iron during acute murine Influenza A/PR/8/34 virus (H1N1) infection. This intracellular pathogen also stimulated hepcidin expression in leukocytes and hepatoma cells. Together, these results indicate that hepcidin induction represents a component of the innate immune response to acute infection, with the potential to affect disease pathogenesis.
authors.affiliation: Molecular Immunology Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Armitage
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Eddowes
authors.forename: Uzi
authors.initials: U
authors.lastname: Gileadi
authors.forename: Suzanne
authors.initials: S
authors.lastname: Cole
authors.forename: Natasha
authors.initials: N
authors.lastname: Spottiswoode
authors.forename: Tharini Ashtalakshmi
authors.initials: TA
authors.lastname: Selvakumar
authors.forename: Ling-Pei
authors.initials: LP
authors.lastname: Ho
authors.forename: Alain R M
authors.initials: AR
authors.lastname: Townsend
authors.forename: Hal
authors.initials: H
authors.lastname: Drakesmith
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000276:immunology* / Q000378:metabolism; D002176:Candida albicans / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology* / Q000378:metabolism; D005408:Flagellin / Q000276:immunology; D056945:Hep G2 Cells; D064451:Hepcidins; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000276:immunology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D023181:Antimicrobial Cationic Peptides; D005408:Flagellin; D064451:Hepcidins; D015850:Interleukin-6; D007378:Interleukins; D050796:STAT3 Transcription Factor; D051198:Toll-Like Receptor 5; D053773:Transforming Growth Factor beta1; D000097043:Interleukin-22; C578702:HAMP protein, human; C579599:Hamp protein, mouse; C508600:IL6 protein, human; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C495346:TLR5 protein, human