DIFFERENTIAL-EFFECTS OF TUMOR-NECROSIS-FACTOR AND ASBESTOS FIBERS ON MANGANESE SUPEROXIDE-DISMUTASE INDUCTION AND OXIDANT-INDUCED CYTOTOXICITY IN HUMAN MESOTHELIAL CELLS

We compared induction of manganese superoxide dismutase (MnSOD) by asb estos fibers and tumor necrosis factor alpha (TNF) using cultured huma n mesothelial cells. Transformed pleural mesothelial cells (MET 5A) we re exposed for 48 h to amosite asbestos fibers (2 mu g/cm(2)), to TNF (10 ng/ml), and to the combination of these two. TNF and amosite + TNF caused significant MnSOD mRNA upregulation. Similarly MnSOD specific activity was increased by TNF (290% increase) and the amosite + TNF co mbination (313% increase) but not by amosite alone. In cell injury exp eriments, amosite and amosite + TNF exposures caused significant cell. membrane injury when assessed by lactate dehydrogenase release, which was 31% and 57% higher than in the unexposed cells. However, only the amosite + TNF combination caused significant depletion of cellular hi gh-energy nucleotide when expressed as percentage of [C-14]adenine lab eling in cellular high-energy nucleotides. The nucleotide levels were 91.5 +/- 2.0% in the unexposed cells, 89.9 +/- 3.9% in amosite-exposed cells, 90.1 +/- 2.2% in TNF-exposed cells, and 79.8 +/- 9.4% in amosi te + TNF-exposed cells. Amosite + TNF-exposed cells were also most sen sitive to menadione (20 mu mol/L, 2 h), a compound which generates sup eroxide radicals intracellularly. In conclusion, our data suggests tha t in human mesothelial cells inflammatory cytokines but not asbestos f ibers alone can cause MnSOD induction. In this study, however amosite asbestos + TNF treatment rendered these cells more vulnerable to oxida nt-induced cell damage despite elevated MnSOD activity.