Tumor necrosis factor-α increases Mn-SOD expression: protection against oxidant injury

B. B. Warner, M. S. Burhans, J. C. Clark, J. R. Wispe

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87 Scopus citations

Abstract

Antioxidant enzymes, including superoxide dismutase, are important for protecting the lung against O2 injury. Manganese superoxide dismutase (Mn-SOD) is a superoxide anion (O2-·) scavenger located in the mitochondria, a primary site of O2-· production during hyperoxia. We studied the effects of tumor necrosis factor (TNF-α), a macrophage-derived cytokine, on Mn-SOD expression in human pulmonary adenocarcinoma cells. TNF-α significantly increased Mn-SOD activity and mRNA in a dose- and time-dependent manner. Mn-SOD activity was increased 3-fold and mRNA 20-fold after a 48-h incubation with TNF-α (25 ng/ml). To examine the mechanism of this increase, cells were incubated for 48 h with TNF-α (25 ng/ml) with or without cycloheximide (10 μM) or actinomycin D (10 μg/ml). Actinomycin D blocked the induction of Mn-SOD mRNA by TNF-α, but cycloheximide did not. These findings suggest that the effect of TNF-α requires gene transcription but not synthesis of new protein intermediates. To test the hypothesis that increased Mn-SOD protects against oxidative injury, pulmonary adenocarcinoma cells were incubated in TNF-α (25 ng/ml) for 48 h and then exposed to paraquat (PQ+), an intracellular O2-· generator. Cells pretreated with TNF-α had significantly improved survival in PQ+ compared with controls. At the LD50 (6 μM) for control cells, 95% of TNF-α-treated cells survived, 85% at the LD75 (10 μM), and 77% at the LD90 (14 μM). Our results suggest that the induction of Mn-SOD by TNF-α in pulmonary adenocarcinoma cells is pretranslationally mediated and that increasing Mn-SOD activity with TNF-α confers protection against O2 radicals.

Original languageEnglish
Pages (from-to)L296-L301
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume260
Issue number4 4-2
StatePublished - 1991

Keywords

  • Actinomycin D
  • Cycloheximide
  • Lung
  • Oxidant injury
  • mRNA

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