title: Repression of repulsive guidance molecule C during inflammation is independent of Hfe and involves tumor necrosis factor-alpha.
abstract: Genetic iron overload, or hemochromatosis, can be caused by mutations in HFE, hemojuvelin, and hepcidin genes. Hepcidin, a negative regulator of intestinal iron absorption, is found to be inappropriately low in both patients and in animal models, indicating that proper control of basal hepcidin levels requires both hemojuvelin and HFE. In mice, repulsive guidance molecule c (Rgmc, the hemojuvelin mouse ortholog) and hepcidin levels are transcriptionally regulated during inflammation. Here, we report that basal Rgmc levels in Hfe-deficient mice are normal and that these mice retain the ability to suppress Rgmc expression after lipopolysaccharide (LPS) challenge. Thus, Rgmc regulation by LPS is Hfe-independent. The response of Rgmc to LPS involves signaling through toll-like receptor 4 (Tlr4), because Tlr4-deficient mice do not show altered Rgmc expression after LPS administration. We further show that tumor necrosis factor-alpha, but not interleukin-6, is sufficient to cause Rgmc down-regulation by LPS. These results contrast with previous data demonstrating that hepcidin levels are directly regulated by interleukin-6 but not by tumor necrosis factor-alpha. The regulation of iron-related genes by different cytokines may allow for time-dependent control of iron metabolism changes during inflammation and may be relevant to chronic inflammation, infections, and cancer settings, leading to the development of anemia of chronic disease.
authors.affiliation: Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Québec, Canada.
authors.forename: Marco
authors.initials: M
authors.lastname: Constante
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wang
authors.forename: Valérie-Ann
authors.initials: VA
authors.lastname: Raymond
authors.forename: Marc
authors.initials: M
authors.lastname: Bilodeau
authors.forename: Manuela M
authors.initials: MM
authors.lastname: Santos
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D058851:GPI-Linked Proteins; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D009124:Muscle Proteins / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D023181:Antimicrobial Cationic Peptides; D058851:GPI-Linked Proteins; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D015850:Interleukin-6; D007501:Iron; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009124:Muscle Proteins; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C578702:HAMP protein, human; C579599:Hamp protein, mouse; C499535:Hfe protein, mouse; C493487:Tlr4 protein, mouse; C504414:HJV protein, mouse