REGULATION OF MANGANESE SUPEROXIDE-DISMUTASE IN GLOMERULAR EPITHELIAL-CELLS - MECHANISMS FOR INTERLEUKIN-1 INDUCTION

Reactive oxygen species have been implicated as mediators of tissue in jury in glomerular inflammation. The expression of the antioxidant enz yme, manganese superoxide dismutase (MnSOD), was examined in primary c ultures of rat glomerular epithelial cells (GEC) in response to inflam matory mediators. The results demonstrate that GEC respond to interleu kin-1 (IL-1) and bacterial lipopolysaccharride (LPS) with an increase in MnSOD steady-state mRNA levels. The IL-1 alpha-mediated induction o f MnSOD mRNA levels was both time- and dose-dependent. Maximal levels, approximately 40-fold above controls, were observed at 12 hours with 2 ng/ml of IL-1 alpha. MnSOD protein levels were also markedly elevate d by IL-1 alpha. The induction of MnSOD mRNA by IL-1 alpha required de novo transcription as well as some degree of protein synthesis. To el ucidate the potential intracellular signal that mediates IL-1 alpha-de pendent MnSOD expression, three classical signaling pathways were exam ined. We found no evidence that MnSOD induction by IL-1 alpha is media ted by either the cyclooxygenase or Lipoxygenase pathway or via activa tion of protein kinase C. Based on the presence of IL-1 alpha in sever al forms of glomerular inflammation, the observed increase in MnSOD ex pression by this immunoregulatory cytokine must have an important role in the antioxidant defense of glomerular epithelial cells.