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Published on: August 16, 2013
Survival pathways triggered by peroxynitrite in cells belonging to the monocyte/macrophage lineage
Orazio Cantoni1, Ilaria Tommasini, Liana Cerioni
1Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino Carlo Bo, Via S. Chiara, Urbino (PU) 27-61029, Italy. cantoni@uniurb.it
Abstract:
Peroxynitrite, a highly reactive nitrogen species, promotes in U937 cells (a promonocytic cell line) a mitochondrial permeability transition (MPT)-dependent necrosis. An initial event triggered by peroxynitrite (i.e., inhibition of complex III of the mitochondrial respiratory chain) is responsible for the time-dependent formation of H(2)O(2), essential for the occurrence of cell death. Otherwise non-toxic concentrations of peroxynitrite nevertheless commit cells to MPT-dependent necrosis, which is however prevented by a cytoprotective signaling driven by arachidonic acid (AA) released by the cytosolic PLA(2) isoform. Interestingly, the mechanism whereby delayed formation of H(2)O(2) promotes toxicity in cells exposed to intrinsically toxic concentrations of peroxynitrite is independent of the accumulation of additional damage. Cell death is in fact mediated by inhibition of the AA-dependent cytoprotective signaling. Exogenous AA, however, prevented toxicity also under these conditions. An additional point to be made is that the major findings obtained using U937 cells were reproduced in different cell types belonging to the monocyte/macrophage lineage. Hence, within the context of the inflammatory response, monocytes and macrophages may cope with peroxynitrite by using AA, a signaling molecule largely available at the inflammatory sites.
Insights
Peroxynitrite induces cell death via mitochondrial damage, but arachidonic acid (AA) offers protection. This AA-mediated defense is crucial for monocytes and macrophages during inflammation.
Area of Science:
- Cellular Biology
- Biochemistry
- Immunology
Background:
- Peroxynitrite is a reactive nitrogen species implicated in cellular damage.
- Mitochondrial dysfunction, specifically the permeability transition (MPT), is a key pathway in cell death.
- Reactive oxygen species like hydrogen peroxide (H2O2) play a role in peroxynitrite-induced toxicity.
Purpose of the Study:
- To investigate the mechanism of peroxynitrite-induced cell death in U937 cells.
- To identify protective signaling pathways against peroxynitrite toxicity.
- To determine the role of arachidonic acid (AA) in mitigating peroxynitrite-induced necrosis.
Main Methods:
- Exposure of U937 cells and other monocyte/macrophage cell types to peroxynitrite.
- Assessment of mitochondrial permeability transition (MPT) and cell death.
- Measurement of hydrogen peroxide (H2O2) formation.
- Evaluation of arachidonic acid (AA) release and its cytoprotective effects.
- Inhibition and supplementation of cytosolic phospholipase A2 (cPLA2) and AA.
Main Results:
- Peroxynitrite triggers MPT-dependent necrosis in U937 cells.
- Inhibition of mitochondrial complex III by peroxynitrite leads to H2O2 formation, essential for cell death.
- Arachidonic acid (AA), released via cPLA2, activates a cytoprotective signaling pathway that prevents necrosis.
- Toxicity at higher peroxynitrite concentrations results from the inhibition of this AA-dependent protective signaling.
- Exogenous AA rescues cells from peroxynitrite-induced death, even when protective signaling is inhibited.
- Findings were validated in other monocyte/macrophage cell types.
Conclusions:
- Peroxynitrite-induced cell death is mediated by mitochondrial dysfunction and H2O2 production.
- Arachidonic acid (AA) acts as a critical endogenous cytoprotective agent against peroxynitrite.
- Monocytes and macrophages utilize AA signaling to counteract peroxynitrite during inflammatory responses.
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