The effects of recombinant tumor necrosis factor (TNF), tumor necrosis serum (TNS), recombinant interleukin 1 (IL-1), and prostaglandin E2 on serum iron parameters and iron handling by macrophages in mice have been investigated. Recombinant TNF caused a significant decrease in serum iron levels after 6 hours, but none of the mediators caused significant changes in total iron binding capacity at this time, although TNS caused a significant increase in total iron binding capacity after 24 hours. Peritoneal macrophages taken from mice 6 hours after inoculation of the mediators were pulsed with 59Fe, 125I-transferrin-antitransferrin immune complexes, and subsequent degradation of the complexes and release of iron were investigated. Both recombinant TNF and TNS caused significant increases in uptake and degradation of the complexes, but with recombinant TNF this was not accompanied by a corresponding increase in iron release. IL-1 and prostaglandin E2 also caused increased degradation of the immune complexes, but uptake of the complexes and iron release were unaffected. When peritoneal macrophages from normal mice were treated with the mediators in vitro and then pulsed with labeled immune complexes, recombinant TNF caused a significant decrease in iron release, but none of the other mediators had any effect. None of the mediators affected uptake or degradation of the immune complexes. These results suggest that TNF, rather than IL-1, mediates the hypoferremia of inflammatory disease and that alterations in the ability of macrophages to handle iron may be responsible.