title: Hemochromatosis protein (HFE) and tumor necrosis factor receptor 2 (TNFR2) influence tissue iron levels: elements of a common gut pathway?
abstract: Quantitative genetic analysis of hepatic and splenic iron levels in recombinant inbred mice yielded a quantitative trait locus that was found to coincide with the genomic locale encompassing the tumor necrosis factor receptor 2 gene (Tnfr2). When fed an iron-enriched diet, mice nullizygous with respect to Tnfr2, but not the Tnfr1 gene, showed a significant increase in splenic non-heme iron levels. This result contrasted with mice deficient in the hemochromatosis protein, HFE, which demonstrated a significant increase in normally high hepatic iron levels, but no change in splenic iron, when fed an iron-enriched chow. Both Tnfr2 knockout and HFE knockout mice fed an iron-enriched diet failed to demonstrate intestinal epithelial cell iron following the application of the Perls' stain, as compared to both Tnfr1 knockout and normal control mice. Moreover, intestinal intraepithelial lymphocytes (IELs) isolated from HFE knockout mice did not show an increase in TNF expression following challenge with the iron-enriched diet, in contrast to normal controls. These results suggest that HFE and TNFR2 are both involved in regulating iron deposition in tissues and that the regulation occurs at the level of the intestine through IEL-orchestrated production of TNF following the binding to TNFR2. These data suggest that HFE and TNFR2 may contribute to a common pathway of the iron stores regulator insuring the controlled efflux of gut iron.
authors.affiliation: H107, Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Meyer
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Gerhard
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Mika
authors.initials: M
authors.lastname: Yoshida
authors.forename: Karen A
authors.initials: KA
authors.lastname: Chorney
authors.forename: John
authors.initials: J
authors.lastname: Beard
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Kauffman
authors.forename: Günter
authors.initials: G
authors.lastname: Weiss
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Chorney
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D040641:Quantitative Trait Loci; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II; D013154:Spleen / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D007501:Iron