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 (RT1c) 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), levels 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.
Brauer
R B
RB
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Baldwin
W M
WM
Wang
D
D
Horwitz
L R
LR
Hess
A D
AD
Klein
A S
AS
Sanfilippo
F
F
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells; D003176:Complement C3 / Q000378:metabolism; D003183:Complement C6 / Q000096:biosynthesis*; D005260:Female; D008099:Liver / Q000378:metabolism*; D016031:Liver Transplantation / Q000276:immunology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D003176:Complement C3; D003183:Complement C6