ANTIOXIDATIVE ROLES OF METALLOTHIONEIN AND MANGANESE SUPEROXIDE-DISMUTASE INDUCED BY TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-6

Antioxidative roles of metallothionein (MT) and manganese superoxide dismutase (Mn-SOD) induced by tumor necrosis factor (TNF) and interleukin 6 (IL-6) have been studied. Since pretreatment of rat with dexamethasone, an inhibitor of cytokine production, prevented MT synthesis induced by paraquat which is a typical superoxide generator, MT synthesis by oxidative stress may be, at least partly, mediated through cytokines. Pretreatment of rat with TNF or IL-6 prevented liver damage and lipid peroxidation caused by carbon tetrachloride. Administration of TNF increased activity of mitochondrial Mn-SOD and concentrations of cytoplasmic MT, but not activities of glutathione peroxidases and Cu,Zn-SOD in the liver. The increment of the Mn-SOD activity and MT was due to the de novo protein synthesis, because gene expression of mRNAs of Mn-SOD and MT in the liver was also induced by TNF and IL-6. These data strongly suggest that MT and Mn-SOD in the liver cooperatively play antioxidative roles. Pretreatment with TNF, however, did not affect the increased levels of plasma fibrinogen and liver MT induced by the following paraquat treatment, although it did prevent lipid peroxidation in the liver. The data suggest that MT is not directly induced by oxygen free radicals. Cytokines may be released by paraquat in tissues other than the liver and induce hepatic synthesis of acute phase proteins including fibrinogen, MT, and Mn-SOD. MT and Mn-SOD induced by cytokines in the liver exert an antioxidative role during acute phase response, therefore preventing tissues from injury by oxidative stress. (C) 1995 Academic Press, Inc.