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 int erleukin 1beta (IL-1beta), tumour necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma) on the iron metabolism of the human monoc ytic cell line U937. Cells were treated with each cytokine for up to 2 4 h, and then iron uptake from diferric transferrin was determined. Th e intracellular distribution of this iron, the expression of the trans ferrin receptor and levels of mRNA for the two ferritin subunits were also studied. IL-1beta, TNFalpha and IFNgamma all decreased transferri n-iron uptake into cells, and all three cytokines had effects on the p roportion of iron associated with ferritin. With TNFalpha there was a marked enhancement of the fraction incorporated into ferritin. Transfe rrin-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-cha in, but not the L-chain; IL-1beta affected mRNA for neither ferritin. These data demonstrate that cytokines, which can be present at high co ncentrations in inflammation, have the capacity to affect macrophage i ron uptake, transferrin receptor expression, intracellular iron handli ng and the relative abundance of ferritin-subunit mRNA, and may theref ore be important mediators in the observed perturbations of iron metab olism in inflammatory diseases.