Dexamethasone differently modulates TNF-alpha- and IL-1 beta-induced transcription of the hepatic Mn-superoxide dismutase gene

The effects of cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and the synthetic glucocorticoid dexamethasone an the gene expression of antioxidant enzymes have been investigated in rat hepatocytes in primary culture, First, we observed that the hepatocyte culture process induced a strong but transient induction of manganese superoxide dismutase (Mn-SOD) gene expression, whereas copper-zinc superoxide dismutase, glutathione peroxidase and catalase genes mere down-regulated, IL-1 beta and TNF-alpha both stimulated specifically Mn-SOD gene expression in a time-dependent manner. TNF-alpha rapidly induced Mn-SOD gene expression while IL-1 beta was a strong but slow inducer of this gene, Both cytokines acted at the transcriptional level as shown by nuclear run on assays, Dexamethasone prevented the TNF-alpha- but not the IL-1 beta-induced up-regulation of Mn-SOD gene transcription by a mechanism likely to involve the glucocorticoid receptor, Moreover this glucocorticoid did not suppress the TNF-alpha-induced increase of NF-kB binding activity. These results suggest that IL-1 beta and TNF-alpha regulate Mn-SOD gene transcription by different pathways, (C) 1997 Federation of European Biochemical Societies.