Previous studies performed in our laboratory indicated that non-toxic concentrations of peroxynitrite nevertheless commit U937 cells to a rapid necrosis that is however prevented by a survival signaling driven by cytosolic phospholipase AZ-released arachidonic acid. Toxicity was mediated by concentrations of peroxynitrite resulting in H2O2-dependent inhibition of arachidonic acid release. The present study shows that U937 cells differentiated to monocytes by prolonged exposure to dimethyl sulfoxide are resistant to peroxynitrite because able to respond with enhanced release of arachidonic acid. An additional important observation was that these cells require more arachidonate than the undifferentiated cells to support the survival signaling. The enhanced arachidonic acid release was not associated with changes in cytosolic phospholipase AZ expression but was rather dependent on the increased responsiveness of the enzyme to calcium-dependent stimulation as well as on reduced mitochondrial formation of H2O2. The latter event was found to be critical, since differentiated and undifferentiated cells were equally sensitive to peroxynitrite when the accumulation of H2O2 was enhanced via depletion of catalase, or addition of a complex III inhibitor. Thus, the strategy selected by the differentiation process to allow monocytes to cope with peroxynitrite appears to involve some specific mechanism preventing the mitochondrial formation of H2O2.
Reduced mitochondrial formation of H(2)O(2) is responsible for resistance of dimethyl sufoxide differentiated U937 cells to peroxynitrite
GUIDARELLI, ANDREA;FIORANI, MARA;CERIONI, LIANA;CANTONI, ORAZIO
2006
Abstract
Previous studies performed in our laboratory indicated that non-toxic concentrations of peroxynitrite nevertheless commit U937 cells to a rapid necrosis that is however prevented by a survival signaling driven by cytosolic phospholipase AZ-released arachidonic acid. Toxicity was mediated by concentrations of peroxynitrite resulting in H2O2-dependent inhibition of arachidonic acid release. The present study shows that U937 cells differentiated to monocytes by prolonged exposure to dimethyl sulfoxide are resistant to peroxynitrite because able to respond with enhanced release of arachidonic acid. An additional important observation was that these cells require more arachidonate than the undifferentiated cells to support the survival signaling. The enhanced arachidonic acid release was not associated with changes in cytosolic phospholipase AZ expression but was rather dependent on the increased responsiveness of the enzyme to calcium-dependent stimulation as well as on reduced mitochondrial formation of H2O2. The latter event was found to be critical, since differentiated and undifferentiated cells were equally sensitive to peroxynitrite when the accumulation of H2O2 was enhanced via depletion of catalase, or addition of a complex III inhibitor. Thus, the strategy selected by the differentiation process to allow monocytes to cope with peroxynitrite appears to involve some specific mechanism preventing the mitochondrial formation of H2O2.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
