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Endocrinology Vol. 141, No. 1 153-162
Copyright © 2000 by The Endocrine Society

ARTICLES

NF-{kappa}B Is Required for Cytokine-Induced Manganese Superoxide Dismutase Expression in Insulin-Producing Cells1

Martine I. Darville, Ye-Shih Ho and Décio L. Eizirik

Diabetes Research Center (M.I.D., D.L.E.), Vrije Universiteit Brussel, B-1090 Brussels, Belgium; and Institute of Chemical Toxicology (Y.-S.H.), Wayne State University, Detroit, Michigan 48201

Address all correspondence and requests for reprints to: Martine I. Darville, Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan, 103, B-1090-Brussels, Belgium. E-mail: mdarv{at}mebo.vub.ac.be

Reactive oxygen species play an important role in the cytotoxic effect of inflammatory cytokines on pancreatic ß-cells in type 1 diabetes mellitus. The antioxidant enzyme manganese superoxide dismutase (MnSOD) is part of the cellular defenses against these deleterious radicals. MnSOD gene expression is induced by cytokines in insulin-producing cells, but the transcriptional regulation of MnSOD expression in these cells is not well understood. In this report, we investigated the transcriptional regulation by cytokines of the rat MnSOD gene in insulin-producing cells. By transient transfections with promoter-luciferase reporter constructs, we identified two interleukin (IL)-1ß-responsive elements, conferring each an additive 3-fold IL-1ß-induced transcriptional activity. The first is located in the promoter region, whereas the second is located in the second intron of the MnSOD gene. Interestingly, the intronic element is required for interferon-{gamma}-induced potentiation. Site-directed mutagenesis and band-shift assays showed that an NF-{kappa}B binding site in each region is necessary, but not sufficient, for transcriptional induction by IL-1ß. Our results suggest that NF-{kappa}B may cooperate with CCAAT/enhancer-binding protein factors in the promoter region and with octamer and Ets factors in the intronic region.




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