INDUCTION OF MNSOD GENE-EXPRESSION IN A HEPATIC MODEL OF TNF-ALPHA TOXICITY DOES NOT RESULT IN INCREASED PROTEIN

The model of toxic liver injury was used to examine the role of mangan ese superoxide dismutase (MnSOD) expression in cellular resistance to tumor necrosis factor (TNF)-alpha toxicity. The effects of the hepatot oxin D-galactosamine (GalN) and lipopolysaccharide (LPS) on hepatic an d splenic TNF-alpha and MnSOD expression were studied. Treatment with GalN and LPS alone or in combination led to equivalent increases in he patic and splenic TNF-alpha gene expression. Hepatic MnSOD mRNA levels were not affected by GalN or GalN with LPS but were increased 13-fold by LPS alone. Splenic MnSOD mRNA levels were increased twofold by Gal N and 13-fold by either LPS alone or GalN plus LPS. The determination of MnSOD protein content, however, revealed no changes in hepatic or s plenic steady-state levels of the protein with any of the treatments, despite the marked increases in MnSOD gene expression. Hepatic MnSOD e nzyme activity was also unchanged by LPS or GalN plus LPS administrati on. Biosynthesis of MnSOD protein in rat hepatocytes isolated from an in vivo LPS-treated rat was unchanged compared with control. MnSOD mRN A levels were increased when GalN treatment was combined with uridine rescue, but again no change in protein was seen. The lack of any incre ase in MnSOD protein after GalN or LPS administration indicates that M nSOD upregulation is not involved in cellular resistance against TNF-o l cytotoxicity in the liver in vivo.