Dexamethasone differently modulates TNF-alpha- and IL-1beta-induced transcription of the hepatic Mn-superoxide dismutase gene.
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.
Antras-Ferry
J
J
Unité Détoxication et Réparation Tissulaire INSERM 456, Faculté desSciences Pharmaceutiques et Biologiques, Université de Rennes I, France. antras@univ-rennes1.fr
Mahéo
K
K
Morel
F
F
Guillouzo
A
A
Cillard
P
P
Cillard
J
J
D000418:Albumins / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002374:Catalase / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000187:drug effects / Q000235:genetics; D017403:In Situ Hybridization; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D013482:Superoxide Dismutase / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000418:Albumins; D005938:Glucocorticoids; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase