{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:53:42Z","timestamp":1791298422539,"version":"4.1.0"},"reference-count":51,"publisher":"American Society of Hematology","issue":"10","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2003,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Under chronic inflammatory conditions cytokines induce a diversion of iron traffic, leading to hypoferremia and retention of the metal within the reticuloendothelial system. However, the regulatory pathways underlying these disturbances of iron homeostasis are poorly understood. We investigated transferrin receptor (TfR)\u2013dependent and \u2013independent iron transport mechanisms in cytokine-stimulated human monocytic cell lines THP-1 and U937. Combined treatment of cells with interferon-\u03b3 (IFN-\u03b3) and lipopolysaccharide (LPS) reduced TfR mRNA levels, surface expression, and iron uptake, and these effects were reversed by interleukin-10 (IL-10), thus stimulating TfR-mediated iron acquisition. IFN-\u03b3 and LPS dose-dependently increased the cellular expression of divalent metal transporter-1, a transmembrane transporter of ferrous iron, and stimulated the uptake of nontransferrin bound iron (NTBI) into cells. At the same time, IFN-\u03b3 and LPS down-regulated the expression of ferroportin mRNA, a putative iron exporter, and decreased iron release from monocytes. Preincubation with IL-10 partly counteracted these effects. Our results demonstrate that the proinflammatory stimuli IFN-\u03b3 and LPS increase the uptake of NTBI via stimulation of divalent metal transporter-1 expression and cause retention of the metal within monocytes by down-regulating ferroportin synthesis. Opposite, the anti-inflammatory cytokine IL-10 stimulates TfR-mediated iron uptake into activated monocytes. The regulation of iron transport by cytokines is a key mechanism in the pathogenesis of anemia of chronic disease and a promising target for therapeutic intervention.<\/jats:p>","DOI":"10.1182\/blood-2002-08-2459","type":"journal-article","created":{"date-parts":[[2003,5,5]],"date-time":"2003-05-05T19:24:00Z","timestamp":1052162640000},"page":"4148-4154","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":336,"title":["Cytokine-mediated regulation of iron transport in human monocytic cells"],"prefix":"10.1182","volume":"101","author":[{"given":"Susanne","family":"Ludwiczek","sequence":"first","affiliation":[{"name":"From the Department of Internal Medicine, University Hospital, Innsbruck, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elmar","family":"Aigner","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, University Hospital, Innsbruck, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Theurl","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, University Hospital, Innsbruck, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gu\u0308nter","family":"Weiss","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, University Hospital, Innsbruck, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2019111702502470400_B1","first-page":"353","article-title":"Iron in infection, immunity, inflammation and neoplasia.","volume-title":"Iron Metabolism in Health and Disease.","author":"Brock","year":"1994"},{"key":"2019111702502470400_B2","doi-asserted-by":"crossref","first-page":"S70","DOI":"10.1046\/j.1365-2362.2002.0320s1070.x","article-title":"Iron and immunity: a double edged sword.","volume":"31","author":"Weiss","year":"2002","journal-title":"Eur J Clin Invest."},{"key":"2019111702502470400_B3","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1159\/000419357","article-title":"Iron and lymphocytes: reciprocal regulatory interactions.","volume":"58","author":"De Sousa","year":"1992","journal-title":"Curr Stud Hematol Blood Transfus."},{"key":"2019111702502470400_B4","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1096\/fasebj.9.2.7540156","article-title":"Free radicals and phagocytic cells.","volume":"9","author":"Rosen","year":"1995","journal-title":"FASEB J."},{"key":"2019111702502470400_B5","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1084\/jem.180.3.969","article-title":"Iron regulates nitric oxide synthase activity by controlling nuclear transcription.","volume":"180","author":"Weiss","year":"1994","journal-title":"J Exp Med."},{"key":"2019111702502470400_B6","doi-asserted-by":"crossref","first-page":"2565","DOI":"10.1182\/blood.V91.7.2565","article-title":"Response of monocyte iron regulatory protein activity to inflammation: abnormal behavior in genetic hemochromatosis.","volume":"91","author":"Recalcati","year":"1998","journal-title":"Blood."},{"key":"2019111702502470400_B7","doi-asserted-by":"crossref","first-page":"12638","DOI":"10.1016\/S0021-9258(18)37801-3","article-title":"The molecular cloning and characterization of ferritin heavy chain, a tumor necrosis factor inducible gene.","volume":"263","author":"Torti","year":"1988","journal-title":"J Biol Chem."},{"key":"2019111702502470400_B8","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1182\/blood.V87.6.2525.bloodjournal8762525","article-title":"Ferritin translation by interleukin-1 and interleukin-6: the role of sequences upstream of the start codons of the heavy and light subunit genes.","volume":"87","author":"Rogers","year":"1996","journal-title":"Blood."},{"key":"2019111702502470400_B9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0070-2137(97)80001-5","article-title":"Regulation of iron metabolism in eukaryotes.","volume":"35","author":"Rouault","year":"1997","journal-title":"Curr Top Cell Regul."},{"key":"2019111702502470400_B10","doi-asserted-by":"crossref","first-page":"8175","DOI":"10.1073\/pnas.93.16.8175","article-title":"Molecular control of vertebrate iron metabolism: mRNA based regulatory circuits operated by iron, nitric oxide and oxidative stress.","volume":"93","author":"Hentze","year":"1996","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2019111702502470400_B11","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1146\/annurev.nutr.20.1.627","article-title":"Iron regulatory proteins and the molecular control of mammalian iron metabolism.","volume":"20","author":"Eisenstein","year":"2000","journal-title":"Ann Rev Nutr."},{"key":"2019111702502470400_B12","doi-asserted-by":"crossref","first-page":"3643","DOI":"10.1002\/j.1460-2075.1993.tb06038.x","article-title":"Biosynthesis of nitric oxide activates iron regulatory factor in macrophages.","volume":"12","author":"Drapier","year":"1993","journal-title":"EMBO J."},{"key":"2019111702502470400_B13","doi-asserted-by":"crossref","first-page":"3651","DOI":"10.1002\/j.1460-2075.1993.tb06039.x","article-title":"Translational regulation via iron-responsive elements by the nitric oxide\/NO-synthase pathway.","volume":"12","author":"Weiss","year":"1993","journal-title":"EMBO J."},{"key":"2019111702502470400_B14","doi-asserted-by":"crossref","first-page":"2917","DOI":"10.1002\/j.1460-2075.1995.tb07291.x","article-title":"Rapid responses to oxidative stress mediated by iron regulatory protein.","volume":"14","author":"Pantopoulos","year":"1995","journal-title":"EMBO J."},{"key":"2019111702502470400_B15","doi-asserted-by":"crossref","first-page":"420","DOI":"10.4049\/jimmunol.158.1.420","article-title":"Pathways for the regulation of macrophage iron metabolism by the anti-inflammatory cytokines IL-4 and IL-13.","volume":"158","author":"Weiss","year":"1997","journal-title":"J Immunol."},{"key":"2019111702502470400_B16","first-page":"319","article-title":"Induction of hypoferremia and modulation of macrophage iron metabolism by tumor necrosis factor.","volume":"61","author":"Alvarez-Hernandez","year":"1989","journal-title":"Lab Invest."},{"key":"2019111702502470400_B17","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1042\/bj2960175","article-title":"Modulation of iron metabolism in monocyte cell line U937 by inflammatory cytokines: changes in transferrin uptake, iron handling and ferritin mRNA.","volume":"296","author":"Fahmy","year":"1993","journal-title":"Biochem J."},{"key":"2019111702502470400_B18","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/41343","article-title":"Cloning and characterization of a mammalian proton-coupled metal-ion transporter.","volume":"388","author":"Gunshin","year":"1997","journal-title":"Nature."},{"key":"2019111702502470400_B19","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/ng0897-383","article-title":"Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene.","volume":"16","author":"Fleming","year":"1997","journal-title":"Nat Genet."},{"key":"2019111702502470400_B20","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/35001596","article-title":"Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter.","volume":"403","author":"Donovan","year":"2000","journal-title":"Nature."},{"key":"2019111702502470400_B21","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/S1097-2765(00)80425-6","article-title":"A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation.","volume":"5","author":"McKie","year":"2000","journal-title":"Mol Cell."},{"key":"2019111702502470400_B22","doi-asserted-by":"crossref","first-page":"19906","DOI":"10.1074\/jbc.M000713200","article-title":"A novel mammalian iron-regulated protein involved in intracellular iron metabolism.","volume":"275","author":"Abboud","year":"2000","journal-title":"J Biol Chem."},{"key":"2019111702502470400_B23","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1146\/annurev.physiol.64.081501.155838","article-title":"Mechanisms of iron accumulation in hereditary hemochromatosis.","volume":"64","author":"Fleming","year":"2002","journal-title":"Annu Rev Physiol."},{"key":"2019111702502470400_B24","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S1367-5931(02)00307-1","article-title":"Metal transporters and disease.","volume":"6","author":"Andrews","year":"2002","journal-title":"Curr Opin Chem Biol."},{"key":"2019111702502470400_B25","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1172\/JCI9972","article-title":"Of metals, mice, and men: what animal models can teach us about body iron loading.","volume":"105","author":"Anderson","year":"2000","journal-title":"J Clin Invest."},{"key":"2019111702502470400_B26","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1053\/gast.2001.24033","article-title":"Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload.","volume":"120","author":"Zoller","year":"2001","journal-title":"Gastroenterology."},{"key":"2019111702502470400_B27","doi-asserted-by":"crossref","first-page":"G598","DOI":"10.1152\/ajpgi.00371.2001","article-title":"Intestinal expression of genes involved in iron absorption in humans.","volume":"282","author":"Rolfs","year":"2002","journal-title":"Am J Physiol Gastrointest Liver Physiol."},{"key":"2019111702502470400_B28","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1172\/JCI200113468","article-title":"Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene.","volume":"108","author":"Montosi","year":"2001","journal-title":"J Clin Invest."},{"key":"2019111702502470400_B29","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0014-5793(01)03189-1","article-title":"Iron-dependent regulation of the divalent metal ion transporter.","volume":"509","author":"Gunshin","year":"2001","journal-title":"FEBS Lett."},{"key":"2019111702502470400_B30","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1042\/bj3630449","article-title":"Expression of the two mRNA isoforms of the iron transporter Nrmap2\/DMTI in mice and function of the iron responsive element.","volume":"363","author":"Tchernitchko","year":"2002","journal-title":"Biochem J."},{"key":"2019111702502470400_B31","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1073\/pnas.85.7.2171","article-title":"Cytoplasmatic protein binds in vitro to a highly conserved sequence in the 5' untranslated regions of ferritin heavy and light subunit mRNAs.","volume":"85","author":"Leibold","year":"1988","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2019111702502470400_B32","doi-asserted-by":"crossref","first-page":"2962","DOI":"10.1182\/blood.V85.10.2962.bloodjournal85102962","article-title":"Effect of nitric oxide on expression of transferrin receptor and ferritin and on cellular iron metabolism in K562 human erythroleukemia cells.","volume":"85","author":"Oria","year":"1995","journal-title":"Blood."},{"key":"2019111702502470400_B33","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1182\/blood.V94.7.2383.419k20_2383_2389","article-title":"Regulation of iron metabolism in murine J774 macrophages: role of nitric oxide dependent and independent pathways following activation with gamma interferon and lipopolysaccharide.","volume":"94","author":"Mulero","year":"1999","journal-title":"Blood."},{"key":"2019111702502470400_B34","doi-asserted-by":"crossref","first-page":"6220","DOI":"10.1074\/jbc.275.9.6220","article-title":"Effects of interferon-gamma and lipopolysaccharide on macrophage iron metabolism are mediated by nitric oxide-induced degradation of iron regulatory protein 2.","volume":"275","author":"Kim","year":"2000","journal-title":"J Biol Chem."},{"key":"2019111702502470400_B35","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1093\/nar\/20.12.2997","article-title":"Post-transcriptional regulation of transferrin receptor mRNA by IFN gamma.","volume":"20","author":"Bourgeade","year":"1992","journal-title":"Nucleic Acids Res."},{"key":"2019111702502470400_B36","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1096\/fasebj.10.11.8836047","article-title":"Superoxide and hydrogen peroxide-dependent inhibition of iron regulatory protein activity: a protective stratagem against oxidative injury.","volume":"10","author":"Cairo","year":"1996","journal-title":"FASEB J."},{"key":"2019111702502470400_B37","doi-asserted-by":"crossref","first-page":"427","DOI":"10.4049\/jimmunol.155.1.427","article-title":"IFN-\u03b2 selectively down-regulates transferrin receptor expression in human peripheral blood macrophages by a post-translational mechanism.","volume":"155","author":"Testa","year":"1995","journal-title":"J Immunol."},{"key":"2019111702502470400_B38","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1053\/gast.2001.29617","article-title":"Molecular aspects of iron absorption and HFE expression.","volume":"121","author":"Parkkila","year":"2001","journal-title":"Gastroenterology."},{"key":"2019111702502470400_B39","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1093\/hmg\/10.20.2181","article-title":"Recent advances in disorders of iron metabolism: mutations, mechanisms and modifiers.","volume":"10","author":"Roy","year":"2001","journal-title":"Hum Mol Genet."},{"key":"2019111702502470400_B40","doi-asserted-by":"crossref","first-page":"6586","DOI":"10.1046\/j.1432-1327.2000.01752.x","article-title":"Interferon-gamma and lipopolysaccharide regulate the expression of Nramp2 and increase the uptake of iron from low relative molecular mass complexes by macrophages.","volume":"267","author":"Wardrop","year":"2000","journal-title":"Eur J Biochem."},{"key":"2019111702502470400_B41","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1126\/science.1057206","article-title":"An iron-regulated ferric reductase associated with the absorption of dietary iron.","volume":"291","author":"McKie","year":"2001","journal-title":"Science."},{"key":"2019111702502470400_B42","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1146\/annurev.micro.56.012302.160847","article-title":"Transition metal in yeast.","volume":"56","author":"Van Ho","year":"2002","journal-title":"Annu Rev Microbiol."},{"key":"2019111702502470400_B43","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1201\/9780824744175.ch19","article-title":"Iron acquisition by the reticuloendothelial system.","volume-title":"Molecular and Cellular Iron Transport.","author":"Weiss","year":"2002"},{"key":"2019111702502470400_B44","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/5979","article-title":"Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse.","volume":"21","author":"Vulpe","year":"1999","journal-title":"Nat Genet."},{"key":"2019111702502470400_B45","first-page":"351","article-title":"The anaemia of chronic disorders.","volume":"3","author":"Cartwright","year":"1966","journal-title":"Semin Hematol."},{"key":"2019111702502470400_B46","first-page":"111","article-title":"The anaemia of inflammation and chronic disease.","volume-title":"Iron in Immunity, Cancer and Inflammation. Chichster","author":"Konjin","year":"1989"},{"key":"2019111702502470400_B47","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1182\/blood.V80.7.1639.1639","article-title":"Progress in understanding the pathogenesis of the anaemia of chronic disease.","volume":"80","author":"Means","year":"1992","journal-title":"Blood."},{"key":"2019111702502470400_B48","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1054\/blre.2002.0193","article-title":"Pathogenesis and treatment of anaemia of chronic disease.","volume":"16","author":"Weiss","year":"2002","journal-title":"Blood Rev."},{"key":"2019111702502470400_B49","doi-asserted-by":"crossref","first-page":"2617","DOI":"10.1182\/blood-2002-04-1182","article-title":"Iron transporter Nramp2\/DMT-1 is associated with the membrane of phagosomes in macrophages and Sertoli cells.","volume":"100","author":"Jabado","year":"2002","journal-title":"Blood."},{"key":"2019111702502470400_B50","doi-asserted-by":"crossref","first-page":"2511","DOI":"10.1182\/blood.V92.7.2511","article-title":"Iron release from human monocytes after erythrophagocytosis in vitro: an investigation in normal subjects and hereditary hemochromatosis patients.","volume":"92","author":"Moura","year":"1998","journal-title":"Blood."},{"key":"2019111702502470400_B51","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.4049\/jimmunol.169.4.2204","article-title":"Role of IL-10 for induction of anemia during inflammation.","volume":"169","author":"Tilg","year":"2002","journal-title":"J Immunol."}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/101\/10\/4148\/1261986\/h81003004148.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/101\/10\/4148\/1261986\/h81003004148.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,25]],"date-time":"2023-04-25T17:58:16Z","timestamp":1682445496000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/101\/10\/4148\/19454\/Cytokinemediated-regulation-of-iron-transport-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,5,15]]},"references-count":51,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2003,5,15]]}},"URL":"https:\/\/doi.org\/10.1182\/blood-2002-08-2459","relation":{},"ISSN":["1528-0020","0006-4971"],"issn-type":[{"value":"1528-0020","type":"electronic"},{"value":"0006-4971","type":"print"}],"subject":[],"published":{"date-parts":[[2003,5,15]]}}}