Cell killing and induction of manganous superoxide dismutase by tumor necrosis factor-alpha is mediated by lipoxygenase metabolites of arachidonic acid.
The signalling pathways utilized by tumor necrosis factor-a (TNF) to elicit its actions have been examined in TA1 adipogenic cells. A role for lipoxygenase metabolites of arachidonic acid as mediators of TNF action in the induction of c-fos has been described. In this paper we report that acute cytotoxicity elicited by TNF, in the presence of cycloheximide (CHX), also utilizes this pathway since inhibitors of lipoxygenase action fully prevent TNF/CHX killing of several cell lines. Our data reveal that TNF induction of manganous superoxide dismutase (MnSOD) is also dependent upon lipoxygenase activity. Radical scavengers such as NAC and PDTC prevent TNF/CHX-induced cell killing and reduce MnSOD induction by TNF. Therefore, cell death by TNF/CHX treatment occurs via a pathway in which lipoxygenase products directly or indirectly operate via the generation of superoxide anions.
Chang
D J
DJ
Institute of Biochemistry and Cell Biology, Syntex Research, Palo Alto, CA 94304.
Ringold
G M
GM
Heller
R A
RA
D016475:3T3 Cells; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects*; D003513:Cycloheximide / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D016166:Free Radical Scavengers; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D007700:Kinetics; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D009637:Masoprocol / Q000494:pharmacology*; D051379:Mice; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D002722:Chlorobenzenes
D001095:Arachidonic Acids; D003513:Cycloheximide; D003907:Dexamethasone; D016166:Free Radical Scavengers; D007211:Indoles; D007213:Indomethacin; D007527:Isoenzymes; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D009637:Masoprocol; D013482:Superoxide Dismutase; D014409:Tumor Necrosis Factor-alpha; C060893:MK-886; D002722:Chlorobenzenes