Immunomodulatory effects of plasminogen activators on hepatic fibrogenesis.
Tissue-type plasminogen activators (tPA) and urokinase-type plasminogen activators (uPA) are involved in liver repair. We examined the potential immunomodulatory actions of uPA, tPA and uPA-receptor (uPAR) in carbon-tetrachloride-induced hepatic fibrosis in wild-type (WT), tPA-/-, uPA-/- and uPAR-/- mice. Carbon-tetrachloride treatment increased fibrosis in four groups but significantly less in three knock-out models. Serum cytokines and intrahepatic T cells elevated significantly following fibrosis process in WT animals but not in the knock-out groups. In culture, uPA increased lymphocyte proliferation significantly in WT and uPA-/- but not uPAR-/- animals. Following uPA exposure in vivo, there was CD8 predominance. To isolate uPA's effect on lymphocytes, WT mice were irradiated sublethally and then reconstituted with WT or uPA-/- lymphocytes. In these animals fibrosis was decreased and T cells were reduced in the uPA-/- recipients. Based on these data we postulate that plasminogen activators affect fibrosis in part by liver-specific activation of CD8 subsets that govern the fibrogenic activity of hepatic stellate cells.
Higazi
A A
AA
Department of Clinical Biochemistry, Hadassah University Hospital, Jerusalem, Israel.
El-Haj
M
M
Melhem
A
A
Horani
A
A
Pappo
O
O
Alvarez
C E
CE
Muhanna
N
N
Friedman
S L
SL
Safadi
R
R
D000818:Animals; D002251:Carbon Tetrachloride; D002450:Cell Communication / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D022781:Hepatocytes / Q000276:immunology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D017710:Lymphocyte Transfusion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010960:Plasminogen Activators / Q000235:genetics / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D055293:Receptors, Urokinase Plasminogen Activator; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014916:Whole-Body Irradiation
D016207:Cytokines; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D002251:Carbon Tetrachloride; D010960:Plasminogen Activators