Hepatic acute phase protein synthesis is indirectly regulated by tumor necrosis factor.
It has been proposed that tumor necrosis factor (TNF) is a direct regulator of postinjury hepatic protein synthesis. To test this hypothesis we investigated the total protein and specific acute phase protein synthesis response of murine hepatocytes to stimulation with mu-rTNF-alpha in vivo and in vitro. Total hepatocyte secretory protein synthesis was assessed by incorporation of [35-S] methionine into TCA-precipitated protein; and acute phase protein synthesis was assessed by induction of a 23-kD acute phase protein marker and by suppression of albumin synthesis determined by SDS-PAGE and autoradiography. We found that rTNF in vivo (8,000 units, IP injection) was associated with reduced total hepatocyte secretory protein synthesis (29 +/- 10%), increased synthesis of the 23-kD acute phase reactant (4.1 +/- 1.6-fold), and decreased albumin synthesis (0.68 +/- 0.2-fold) compared to saline-injected control animals. The in vitro stimulation of cultured murine hepatocytes directly with rTNF failed to demonstrate changes in total secretory protein synthesis or 23-kD protein; however, it did result in significant suppression of albumin synthesis (0.82 +/- 0.1-fold). In additional experiments, hepatocytes:nonparenchymal cell co-cultures stimulated with lipopolysaccharide (LPS) demonstrated protein synthesis changes similar to the in vivo TNF response including increased 23-kD protein and decreased albumin synthesis. These co-cultures demonstrated TNF production; however, addition of TNF antiserum during LPS stimulation had no effect on either 23-kD protein or albumin synthesis, despite the complete neutralization of TNF activity in the co-culture supernatants.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Surgery, University of Minnesota Hospitals, Minneapolis.
P E
PE
Bankey
J E
JE
Mazuski
M
M
Ortiz
J M
JM
Fulco
F B
FB
Cerra
D000209:Acute-Phase Proteins / Q000096:biosynthesis*; D000418:Albumins / Q000096:biosynthesis; D000818:Animals; D001345:Autoradiography; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000209:Acute-Phase Proteins; D000418:Albumins; D014409:Tumor Necrosis Factor-alpha