MODULATION OF IRON-METABOLISM IN MONOCYTE CELL-LINE U937 BY INFLAMMATORY CYTOKINES - CHANGES IN TRANSFERRIN UPTAKE, IRON HANDLING AND FERRITIN MESSENGER-RNA

We have investigated the effects of the pro-inflammatory cytokines interleukin 1beta (IL-1beta), tumour necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma) on the iron metabolism of the human monocytic cell line U937. Cells were treated with each cytokine for up to 24 h, and then iron uptake from diferric transferrin was determined. The intracellular distribution of this iron, the expression of the transferrin receptor and levels of mRNA for the two ferritin subunits were also studied. IL-1beta, TNFalpha and IFNgamma all decreased transferrin-iron uptake into cells, and all three cytokines had effects on the proportion of iron associated with ferritin. With TNFalpha there was a marked enhancement of the fraction incorporated into ferritin. Transferrin-receptor expression was diminished by TNFalpha and IL-1beta, but not IFNgamma, suggesting different effector mechanisms. Both TNFalpha and IFN-gamma increased the amount of cellular mRNA for ferritin H-chain, but not the L-chain; IL-1beta affected mRNA for neither ferritin. These data demonstrate that cytokines, which can be present at high concentrations in inflammation, have the capacity to affect macrophage iron uptake, transferrin receptor expression, intracellular iron handling and the relative abundance of ferritin-subunit mRNA, and may therefore be important mediators in the observed perturbations of iron metabolism in inflammatory diseases.