title: A role for tumour necrosis factor alpha in human small bowel iron transport.
abstract: Cytokines are integral to the development of anaemia of chronic inflammation. Cytokines modulate hepcidin expression and iron sequestration by the reticuloendothelial system but their direct effects on small bowel iron transport are not well characterized. The aim of the present study was to examine the local effects of TNFalpha (tumour necrosis factor alpha) on small bowel iron transport and on iron transporter expression in the absence of hepcidin. The effects of TNFalpha on iron transport were determined using radiolabelled iron in an established Caco-2 cell model. The effect of TNFalpha on the expression and localization of the enterocyte iron transporters DMT-1 (divalent metal transporter 1), IREG-1 (iron-regulated transporter 1) and ferritin was determined utilizing Caco-2 cells and in a human ex vivo small bowel culture system. TNFalpha mediated an early induction in both iron import and iron export, which were associated with increased DMT-1 and IREG-1 mRNA and protein expression (P<0.05). However, by 24 h, both iron import and iron export were significantly inhibited, coinciding with an induction of ferritin heavy chain (P<0.05) and a decrease in DMT-1 and IREG-1 to baseline levels. In addition, there was a relocalization of IREG-1 away from the basolateral cell border and increased iron deposition in villous enterocytes. In conclusion, TNFalpha has a direct effect on small bowel iron transporter expression and function, leading to an inhibition of iron transport.
authors.affiliation: Division of Medical Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TH, UK.
authors.forename: Naveen
authors.initials: N
authors.lastname: Sharma
authors.forename: Abas H
authors.initials: AH
authors.lastname: Laftah
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Brookes
authors.forename: Brian
authors.initials: B
authors.lastname: Cooper
authors.forename: Tariq
authors.initials: T
authors.lastname: Iqbal
authors.forename: Chris
authors.initials: C
authors.lastname: Tselepis
mesh_terms: D000328:Adult; D023181:Antimicrobial Cationic Peptides / Q000235:genetics; D001693:Biological Transport, Active / Q000187:drug effects*; D018938:Caco-2 Cells; D027682:Cation Transport Proteins / Q000235:genetics; D003600:Cytosol / Q000378:metabolism; D005293:Ferritins / Q000235:genetics; D005786:Gene Expression Regulation; D064451:Hepcidins; D006801:Humans; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D005293:Ferritins; D064451:Hepcidins; D007501:Iron; D033862:Iron-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2; C578702:HAMP protein, human