MACROPHAGE IS AN IMPORTANT AND PREVIOUSLY UNRECOGNIZED SOURCE OF MACROPHAGE-MIGRATION INHIBITORY FACTOR

For over 25 years, the cytokine known as macrophage migration inhibito ry factor (MIF) has been considered to be a product of activated T lym phocytes. We recently identified the murine homolog of human MIF as a protein secreted by the pituitary in response to endotoxin administrat ion. In the course of these studies, we also detected MIF in acute ser a obtained from endotoxin-treated, T cell-deficient (nude), and hypoph ysectomized mice, suggesting that still more cell types produce MIE He re, we report that cells of the monocyte/macrophage lineage are an imp ortant source of MIF in vitro and in vivo. We observed high levels of both preformed MIF protein and MIF mRNA in resting, nonstimulated cell s. In the murine macrophage cell line RAW 264.7, MIF secretion was ind uced by as little as 10 pg/ml of lipopolysaccharide (LPS), peaked at 1 ng/ml, and was undetectable at LPS concentrations >1 mu g/ml. A simil ar stimulation profile was observed in LPS-treated peritoneal macropha ges; however, higher LPS concentrations were necessary to induce peak MIF production unless cells had been preincubated with interferon gamm a (IFN-gamma). In RAW 264.7 macrophages, MIF secretion also was induce d by tumor necrosis factor alpha (TNF-alpha) and IFN-gamma, but not by interleukins 1 beta or 6. Of note, MIF-stimulated macrophages were ob served to secrete bioactive TNF-alpha. Although previously overlooked, the macrophage is both an important source and an important target of MIF in vivo. The activation of both central (pituitary) and periphera l (macrophage) sources of MIF production by inflammatory stimuli provi des further evidence for the critical role of this cytokine in the sys temic response to tissue invasion.