EXPRESSION OF MACROPHAGE-COLONY-STIMULATING FACTOR AND ITS RECEPTOR IN HEPATIC GRANULOMAS OF KUPFFER-CELL-DEPLETED MICE

In mice administered with liposome-entrapped dichloromethylene diphosp honate, which depletes Kupffer cells, the size and the number of zymos an-induced granulomas in the liver were smaller than in untreated mice . The number of macrophage precursors, as detected by the monoclonal a ntibodies for macrophage precursors, increased after zymosan injection in both groups of mice, proliferated, and differentiated into macroph ages. Expression of macrophage colony-stimulating factor (M-CSF), inte rleukin-1, monocyte chemoattractant protein-1, tumor necrosis factor-a lpha, and interferon-gamma mRNA was enhanced in the stage of granuloma formation in the control mouse liver, whereas it was suppressed in Ku pffer-cell-depleted mice. However, M-CSF mRNA expression was increased in the Kupffer-cell-depleted mice to form granulomas in the late stag es. In situ hybridization demonstrated the expression of M-CSF mRNA an d c-fms mRNA in Kupffer cells and monocyte-derived macrophages in the sinusoid and granulomas. The concentration of M-CSF in serum of zymosa n-injected control mice was within normal range, but that of zymosan-t reated or untreated Kupffer-cell-depleted mice was markedly elevated a t day 1. These findings imply that Kupffer cells are indispensable for granuloma formation and produce various cytokines including M-CSF. Th e local production and consumption of M-CSF in the liver may play a cr ucial role in granulomtous inflammation.