Relationship between TNF-alpha and iron metabolism in differentiating human monocytic THP-1 cells

The human monocytic cell line THP-1 differentiates along the macrophage lin e after phorbol-12-myristate-13-acetate (PMA) supplementation and can be st imulated to secrete tumour necrosis factor alpha (TNF-alpha) by interferon gamma (IFN-gamma) addition. We found that, in the early stage of differenti ation (1-48 h), PMA induction elicited an upregulation of intracellular H f erritin and H ferritin binding sites and a downregulation of transferrin re ceptor. In addition, we found that iron administration to PMA-differentiati ng cells induced the expression of TNF-alpha mRNA and TNF-alpha secretion t o levels even higher than those induced by IFN-gamma alone. The iron chelat or desferrioxamine showed the opposite effect and reduced TNF-alpha release . In contrast, preincubation of the cells with iron before PMA induction re sulted in a decrease of the TNF-alpha secretion induced by IFN-gamma, where as the opposite was true after preincubation with desferrioxamine. The data support a co-ordinate interaction between iron and TNF-alpha in monocyte m acrophages, with an iron-mediated upregulation of TNF-alpha in the early ph ase of differentiation and an iron-mediated inhibition at later stages. Thi s complex relationship has to be considered in evaluating the effects of ir on on inflammation.