Hepatic and extrahepatic biosynthesis of complement factor C6 in the rat

The relative contributions of liver and bone marrow (BM) constituents to systemic C6 production were compared in a rat model. Liver grafts were transplanted from C6-sufficient PVG (RT1(c)) rats (PVG (C⁺)) to profoundly C6-deficient PVG rats (PVG (C^-)). C6 levels were restored to 32% within 24 h and reached more than 80% of that of the PVG (C⁺) donor within 7 days post- grafting, which indicates that the liver is a primary source of systemic C6 production. When livers were transplanted from PVG (C^-) to PVG (C⁺) rats (n = 3), level of C6 dropped to 42% of pretransplant levels within 24 h and remained between 30 and 40% for more than 100 days after grafting. To determine the source of extrahepatic C6 production, BM was transplanted from PVG (C⁺) to PVG (C^-) rats after total body irradiation. Levels of C6 increased from undetectable levels to 5% of C6 levels of the donor PVG (C⁺) rat within 60 days. Replenishing PVG (C^-) recipients with BM after treatment of recipients with busulfan, which preferentially allows reconstitution with donor myelomonocyte stem cells, resulted in restoration of C activity. Treatment with cyclophosphamide before BM transplantation, which preferentially allows reconstitution of lymphoid stem cells, did not restore hemolytic C activity in PVG (C^-) rats. These results were confirmed directly by the successful restoration of C activity with BM depleted of lymphocytes by counterflow centrifugal elutriation from PVG (C⁺) rats. These in vivo experiments demonstrate that the liver is a primary, but not the sole, source of C6 in the rat and that extrahepatic sources, such as myelomonocytes, and not lymphoid cells in the BM produce a significant amount of systemic C6 in the rat.