title: IL-22 regulates iron availability in vivo through the induction of hepcidin.
abstract: Iron is a trace element important for the proper folding and function of various proteins. Physiological regulation of iron stores is of critical importance for RBC production and antimicrobial defense. Hepcidin is a key regulator of iron levels within the body. Under conditions of iron deficiency, hepcidin expression is reduced to promote increased iron uptake from the diet and release from cells, whereas during conditions of iron excess, induction of hepcidin restricts iron uptake and movement within the body. The cytokine IL-6 is well established as an important inducer of hepcidin. The presence of this cytokine during inflammatory states can induce hepcidin production, iron deficiency, and anemia. In this study, we show that IL-22 also influences hepcidin production in vivo. Injection of mice with exogenous mouse IgG1 Fc fused to the N terminus of mouse IL-22 (Fc-IL-22), an IL-22R agonist with prolonged and enhanced functional potency, induced hepcidin production, with a subsequent decrease in circulating serum iron and hemoglobin levels and a concomitant increase in iron accumulation within the spleen. This response was independent of IL-6 and was attenuated in the absence of the IL-22R-associated signaling kinase, Tyk2. Ab-mediated blockade of hepcidin partially reversed the effects on iron biology caused by IL-22R stimulation. Taken together, these data suggest that exogenous IL-22 regulates hepcidin production to physiologically influence iron usage.
authors.affiliation: Department of Inflammation, Amgen Inc., Seattle, WA 98119, USA.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Smith
authors.forename: Tara L
authors.initials: TL
authors.lastname: Arvedson
authors.forename: Keegan S
authors.initials: KS
authors.lastname: Cooke
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Dickmann
authors.forename: Carla
authors.initials: C
authors.lastname: Forte
authors.forename: Hongyan
authors.initials: H
authors.lastname: Li
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Merriam
authors.forename: V Kristina
authors.initials: VK
authors.lastname: Perry
authors.forename: Linh
authors.initials: L
authors.lastname: Tran
authors.forename: James B
authors.initials: JB
authors.lastname: Rottman
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Maxwell
mesh_terms: D000595:Amino Acid Sequence; D018798:Anemia, Iron-Deficiency / Q000097:blood / Q000139:chemically induced; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D002478:Cells, Cultured; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D064451:Hepcidins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics; D015850:Interleukin-6 / Q000502:physiology; D007378:Interleukins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology* / Q000633:toxicity; D007501:Iron / Q000097:blood / Q000378:metabolism*; D000090463:Iron Deficiencies; D007589:Job Syndrome / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017452:Receptors, IgG / Q000172:deficiency; D018123:Receptors, Interleukin / Q000819:agonists / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D053634:TYK2 Kinase / Q000172:deficiency / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D000911:Antibodies, Monoclonal; D064451:Hepcidins; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D015850:Interleukin-6; D007378:Interleukins; D007501:Iron; D012333:RNA, Messenger; D017452:Receptors, IgG; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; D053634:TYK2 Kinase; D000097043:Interleukin-22; C578702:HAMP protein, human; C579599:Hamp protein, mouse; C494086:STAT3 protein, human; C415369:interleukin-22 receptor; C577686:interleukin-6, mouse