Severe iron deficiency blunts the response of the iron regulatory gene Hamp and pro-inflammatory cytokines to lipopolysaccharide

Abstract

BackgroundExpression of the key iron regulatory hormone hepcidin is increased by some stimuli (iron loading, inflammation) but decreased by others (increased erythropoiesis, iron deficiency). We investigated the response of hepcidin to increased erythropoiesis and iron deficiency in the presence of an acute inflammation to assess the relative strengths of these stimuli. Design and MethodsSprague-Dawley rats were maintained on control or iron-deficient diets and treated with lipopolysaccharide to induce inflammation or phenylhydrazine to stimulate erythropoiesis. The levels of Hamp, IL-6 and a2m mRNA were determined by qualitative real-time polymerase chain reaction and those of serum interleukin-6 and tumor necrosis factor-a were measured by enzyme-linked immunosorbent assay. Cultured RAW264.7 and HuH7 cells were used in associated studies. ResultsThe increase in hepatic hepcidin levels induced by lipopolysaccharide was not affected by phenylhydrazine treatment but was blunted by iron deficiency. Lipopolysaccharide-treated iron-deficient animals also showed lower liver a2m mRNA and reduced serum interleukin-6 and tumor necrosis factor-a, suggesting a more generalized effect of iron deficiency. Similarly, RAW 264.7 cells treated with iron chelators and then stimulated with lipopolysaccharide showed lower IL-6 mRNA than cells treated with lipopolysaccharide alone. Huh7 cells treated with an iron chelator showed a blunted hepcidin response to interleukin-6, suggesting that the response of hepatic parenchymal cells to inflammatory cytokines may also be iron-dependent. ConclusionsIn any one physiological situation, net hepcidin levels are determined by the relative strengths of competing stimuli. The ability of severe iron deficiency to blunt the response to lipopolysaccharide of both hepcidin and other markers of inflammation suggests that adequate iron levels are necessary for a full acute phase response.Key words: hepcidin, a2m, erythropoiesis, iron, inflammation. Hamp and pro-inflammatory cytokines to lipopolysaccharide. Haematologica 2010;95(10):1660-1667. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Darshan D, Frazer DM, Wilkins SJ, and Anderson GJ. Severe iron deficiency blunts the response of the iron regulatory gene Severe iron deficiency blunts the response of the iron regulatory gene

Hepcidin in Human Iron Disorders: Diagnostic Implications

“…This algorithm provided insight into the interrelation of these pathways by showing that hepcidin inhibition by erythropoiesis strongly interferes with hepcidin upregulation by iron and that inflammation strongly increases hepcidin regardless of iron status and erythropoietic activity. These findings are in agreement with results of studies demonstrating that high erythroid demand for iron blunts hepcidin induction by a concomitant inflammatory response (50,(72)(73)(74)(75). Other studies have shown that increased and/or ineffective erythropoiesis blunts the induction of hepcidin by increased body iron stores (52,73 ).…”

Combinatorial effects of malaria season, iron deficiency, and inflammation determine plasma hepcidin concentration in African children

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Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses

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