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Dexamethasone Promotes Toxicity in U937 Cells Exposed to Otherwise Nontoxic Concentrations of Peroxynitrite: Pivotal Role for Lipocortin 1-Mediated Inhibition of Cytosolic Phospholipase A₂

Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino "Carlo Bo", Urbino, Italy

Pretreatment with dexamethasone (Dex) was not toxic for U937 cells but caused a rapid lethal response upon subsequent exposure to otherwise nontoxic concentrations of peroxynitrite. This effect was not associated with enhanced formation of hydrogen peroxide taking place after peroxynitrite and was shown previously to play a pivotal role in the ensuing lethal response. Further analyses revealed that although Dex did not affect cytosolic phospholipase A₂ (cPLA₂) expression, it markedly reduced the extent of arachidonic acid (AA) release mediated by peroxynitrite-dependent stimulation of cPLA₂. This event, as well as the enhanced toxicity, was abolished by mifepristone, a glucocorticoid receptor antagonist. The outcome of various approaches, using phospholipase A₂ inhibitors, cPLA₂ antisense oligonucleotide-transfected cells, and supplementation with exogenous AA, led to the demonstration that inhibition of cPLA₂ activity is causally linked to the increased susceptibility to peroxynitrite caused by Dex. Finally, the effects of Dex were shown to be mediated by enhanced expression of lipocortin 1 (LC1), a cPLA₂ inhibitory protein. These results indicate that Dex promotes toxicity in U937 cells exposed to otherwise nontoxic concentrations of peroxynitrite and that this event is causally linked to enhanced expression of LC1 leading to inhibition of cPLA₂. Thus, the increased lethal response arises because of LC1-dependent impairment of the AA-induced cytoprotective mechanism triggered by peroxynitrite.

Received October 8, 2003; accepted January 13, 2004.

Address correspondence to: Prof. Orazio Cantoni, Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino "Carlo Bo", Via S. Chiara, 27-61029 Urbino (PU) Italy. E-mail: cantoni{at}uniurb.it

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