ムラミルペプチドによるモルモットマクロファージの活性化と分化に関する研究

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  • Activation and Differentiation of Guinea pig Macrophage by Muramy Dipeptide

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Muramyl dipeptide (MDP) is a minimal structure necessory for various biological activities of bacterial cell wall peptidoglycans. MDP induces in guinea pigs the granulomas containing macrophages and epithelioid cells differentiated from macrophages. This suggests that MDP differentiates macrophages into epithelioid cells. This study was undertaken to gain an insight into the mechanism of activation and differentiation of macrophage induced by MDP. For this purpose, the effect of MDP on macrophage DNA synthesis was studied in view of the generally accepted fact that DNA synthesis is decreased when cells differentiate. Guinea pig peritoneal exudate macrophages actively incorporated ^3H-thymidine into trichloroacetic acidin soluble fraction in vitro without macrophage proliferating factors. The incorporation of ^3H-Thymidine was almost completely inhibited by aphidicolin, an inhibitor of DNA polymerase-α and an autoradiograph showed heavy labeling in nuclei of about 200% of macrophage populations. These results indicate that the observed thymidine incorporation reflected a DNA synthesis for replication. When macrophage was stimulated by MDP, the ^3H-Thymidine incorporation was markedly suppressed while ^<14>C-glucosamine incorporation and production of monokine were increased. The suppression of ^3H-thymidine incorporation by MDP was not due to the decrease in thymidine transport through the cell membrane. An autoradiograph revealed that MDP decreased markedly the number of macrophages whose nuclei were labeled by ^3H-Thymidine. These resuts indicate that suppresion of ^3H-thymidine incorporation by MDP was due to a true inhibition of DNA synthesis. Among the three tested enzymes involved in DNA synthesis, only thymidine kinase activity decreased progressively in parallel with the decline in ^3H-Thymidine incorporation. Cyclic AMP and PGE_2,both of which are increased in amount in macrophage by MDP stimulation, suppressed DNA synthesis of macrophage. Phorbol myristic acid (PMA), ionomycin and debutyryl cyclic GMP failed to affect the ^3H-Thymidine incorporation. Inhibitors of cyclic AMP-dependent protein kinase considerably reduced the suppressive effect on ^3H-Thymidine incorporation. These results suggest that cyclic AMP or cyclic AMP-dependent protein kinase might be play an important role in suppression of ^3H-Thymidine incorporation. Concerning various analogs of MDP, a close correlation was observed among the capacities of activating macrophages, suppressing DNA synthesis and inducing epithelioid granuloma formation. These findings suggest that suppression of DNA synthesis by MDP may be induced by macrophage activation and represent an initial event during the differentiation of macrophage for epithelioid cells.

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