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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.

SUBMITTER: Sharma N

PROVIDER: S-EPMC1198923 | biostudies-other | 2005 Sep

REPOSITORIES: biostudies-other

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Project description:BackgroundThe humoral system is activated and various cytokines are released due to infections in tissues and traumatic damage. Nuclear factor-kappa B dimers are encoded by nuclear factor-kappa B genes and regulate transcription of several crucial proteins of inflammation such as tumour necrosis factor-alpha.AimsTo investigate the possible effect of polymorphisms on tumour necrosis factor-alpha serum levels with clinical and prognostic parameters of sepsis by determining the nuclear factor-kappa B-1-94 ins/del ATTG and tumour necrosis factor-alpha (-308 G/A) gene polymorphisms and tumour necrosis factor-alpha serum levels.Study designCase-control study.MethodsSeventy-two patients with sepsis and 104 healthy controls were included in the study. In order to determine the polymorphisms of nuclear factor-kappa B-1-94 ins/del ATTG and tumour necrosis factor-alpha (-308 G/A), polymerase chain reaction-restriction fragment length polymorphism analysis was performed and serum tumour necrosis factor-alpha levels were determined using an enzyme-linked immunosorbent assay.ResultsWe observed no significant differences in tumour necrosis factor-alpha serum levels between the study groups. In the patient group, an increase in the tumour necrosis factor-alpha serum levels in patients carrying the tumour necrosis factor-alpha (-308 G/A) A allele compared to those without the A allele was found to be statistically significant. Additionally, an increase in the tumour necrosis factor-alpha serum levels in patients carrying tumour necrosis factor-alpha (-308 G/A) AA genotype compared with patients carrying the AG or GG genotypes was statistically significant. No significant differences were found in these 2 polymorphisms between the patient and control groups (p>0.05).ConclusionOur results showed the AA genotype and the A allele of the tumour necrosis factor-alpha (-308 G/A) polymorphism may be used as a predictor of elevated tumour necrosis factor-alpha levels in patients with sepsis.

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

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