The role of macrophage colony-stimulating factor in the differentiation and proliferation of Kupffer cells in the liver of protein-deprived mice.

BACKGROUND

Protein calorie malnutrition is known to induce various macrophage dysfunctions, such as the impairment of their phagocytic function, proliferative capacity, and bactericidal activity. However, little is known about the behavior of Kupffer cells under protein calorie malnutrition in vivo.

EXPERIMENTAL DESIGN

To investigate the behavior of Kupffer cells under protein calorie malnutrition, we fed mice on a low protein (protein-derived) diet for 4 weeks and examined the number, cytologic changes, and proliferative capacity of their Kupffer cells. To detect macrophage precursor cells, colony-forming assays were performed in the bone marrow, spleen, and liver of the mice. To investigate the relationship of Kupffer cells to CSF, the serum levels of IL-6 and granulocyte-macrophage colony-stimulating factor were measured by ELISA, and the expression of macrophage colony-stimulating factor (M-CSF) mRNA in the liver was determined by Northern blot analysis. The recovery processes of Kupffer cells in the protein-deprived mice after normal protein feeding or daily recombinant human macrophage colony-stimulating factor administration were also investigated.

RESULTS

In the protein-deprived mice, Kupffer cells decreased in number to two-thirds that of the normally fed (nondeprived) mice, showed the cytologic and ultrastructural features of maturation failure, and had reduced proliferative capacity. After normal protein feeding or recombinant human macrophage colony-stimulating factor administration, the number, morphology, and proliferative capacity of the Kupffer cells in the liver returned to normal, and they matured as in the nondeprived mice. In the protein-deprived mice, the serum levels of IL-6 and granulocyte-macrophage colony-stimulating factor increased, and the expression of M-CSF mRNA in the liver was reduced. In the bone marrow, the granulocyte-macrophage colony-forming cells and macrophage colony-forming cells were increased, and the influx of monocytes into the liver was temporarily enhanced; however, the number of monocytes in the peripheral blood was decreased.

CONCLUSIONS

These results suggest that the reduced production of M-CSF in the liver of protein-deprived mice results in numerical reduction, maturation failure, and decreased proliferative capacity of Kupffer cells.