A role for tumour necrosis factor alpha in human small bowel iron transport

Neil Sharma, Abas Laftah, Matthew Brookes, Brian Cooper, Tariq Iqbal, Chris Tselepis

Research output: Contribution to journalArticle

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 TNF alpha (tumour necrosis factor a) on small bowel iron transport and on iron transporter expression in the absence of hepcidin. The effects of TNF alpha on iron transport were determined using radiolabelled iron in an established Caco-2 cell model. The effect of TNFa 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. TNF alpha 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, TNF alpha has a direct effect on small bowel iron transporter expression and function, leading to an inhibition of iron transport.
Original languageEnglish
Pages (from-to)437-446
Number of pages10
JournalBiochemical Journal
Volume390(Pt 2)
Publication statusPublished - 1 Sep 2005

Keywords

  • Caco-2 cell
  • cytokine
  • anaemia
  • small bowel
  • tumour necrosis factor alpha
  • iron transport

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