Cholesterol loading of macrophages, such as occurs in atheroma foam cells, has recently been shown to upregulate a novel receptor activity that mediates the internalization degradation of the atherogenic lipoprotein, lipoprotein(a) (Lp(a)), and its protein moiety, apoprotein(a), (apo(a)). Herein, the regulation of this receptor activity by macrophage activation and interferon-gamma (IFN-gamma) was investigated. Compared with control foam cells, 125I-recombinant-apo(a) (r-apo(a)) degradation assayed after 5 h of incubation was 3-6-fold less in foam cells derived from thioglycollate- or concanavalin A-elicited mouse peritoneal macrophages. In vitro treatment of foam cells derived from resident mouse peritoneal macrophages or from human monocyte-derived macrophages with IFN-gamma also led to a substantial decrease in the ability of these cells to degrade 125I-rapo(a); similar results were obtained with 125I-Lp(a). In contrast, IFN-gamma-treated foam cells that were incubated for 10 min with 125I-r-apo(a) and then chased for 2 h in the absence of ligand degraded similar amounts of 125I-r-apo(a) as untreated foam cells. To reconcile these data, we hypothesized that the apo(a) receptor activity undergoes ligand-induced recycling and that IFN-gamma disrupts this recycling. To test this idea, control and IFN-gamma-treated foam cells were incubated for 10 min with unlabeled r-apo(a), and then 125I-r-apo(a) receptor activity was assayed at various times thereafter. Untreated foam cells showed clear evidence of ligand-induced recycling of the apo(a) receptor activity, whereas recycling was markedly diminished in the IFN-gamma-treated foam cells. Thus, by disrupting ligand-induced receptor recycling, IFN-gamma leads to down-regulation of the foam cell Lp(a)/apo(a) receptor activity. Since T cells are known to be present in atherosclerotic lesions, these findings raise the possibility that the degradation by atheroma foam cells of Lp(a) and other possible ligands for the receptor may be reversibly regulated by IFN-gamma.