A role of marcrophage colony-stimulating factor (M-C SF) in macrophage diferentiation

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Since the obteopertrotic (op/op) mice are a'mutation within the coding region of the macrophage colony-stimulating factor (M-CSF) gene, it serves as a model for investigating the differentiation mechanism of macrophage populations. The op/op mice were severely monocytopenic and showed marked reduction of osteoclasts and tissu macrophages. After daily M-CSF injection, the numbers of monocytes , tissue macrophages, and osteoclasts were remarkably increased. These results indicate that M-CSF is a potent inducer of the development and differentation of monocyte/macrophages.We have developed a macrophage depletion method using liposome-entrapped clodronate. By this method Kupffer cells were selectively elimnated in mice. Repopulating small macrophages actively proliferrated and the number of Kupffer cells returned to the normal level by day 14. The numbers of macrophage precursors in the liver increased after Kupffer cell depletion. The precursors proliferated and differentiated into Kupffer cells. M-CSF mRNA expression was enhanced in the liver after Kupffer cell depletion. We then examined the expression of M-CSF and its seceptor in hepatic zymosan-induced granulomas of Kupffer cell-depleted mice.In Kpffer cell-depleted mice, granuloma formation was suppressed. Kupffer cell and monocyte-derived macrophage expressed M-CSF and its receptor in control mice. however, the expression of M-CSF and other cytokines was suppressed in Kupffer cell-depleted mice. These finding imply that local production and inflammation. Local production of M-CSF and the presence of macrophege precursors in the milky spots were also confirmed after depleting omental macrophages by intraperitoneal adminstration of this drug. In conclusion, local production of M-CSF provides microenvironments for the differentiation and proliferation of macrophages.