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

Abstract

The effects of cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and the synthetic glucocorticoid dexamethasone on 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 were down-regulated. IL-1beta 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-1beta 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-1beta 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-kappaB binding activity. These results suggest that IL-1beta and TNF-alpha regulate Mn-SOD gene transcription by different pathways.