The arachidonate-dependent survival signaling preventing toxicity in monocytes/macrophages exposed to peroxynitrite.
Cells belonging to the monocyte/macrophage lineage are in general highly resistant to peroxynitrite. Resistance is not dependent on the scavenging of peroxynitrite itself, or of other secondary reactive species, but is rather associated with the prompt activation of a survival signaling leading to the prevention of toxicity in cells otherwise committed to mitochondrial permeability transition (MPT)-dependent necrosis. The signaling pathway is triggered by cytosolic phospholipase A2-released arachidonic acid, leading to the sequential activation of 5-lipoxygenase (5-LO) and protein kinase C alpha, an event associated with the cytosolic accumulation of Bad. Hence, inhibition of 5-LO (or that of any of the aforementioned enzymes involved in the signaling cascade) was associated with the mitochondrial accumulation of Bad and Bax and with a rapid MPT-dependent toxicity. These results contribute to the definition of the mechanism(s) whereby monocytes/macrophages survive to peroxynitrite in inflamed tissues and provide insights for the development of novel anti-inflammatory therapies based on the suppression of inflammatory cell survival.
Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino Carlo Bo, Urbino, Italy.
Orazio
O
Cantoni
Ilaria
I
Tommasini
Liana
L
Cerioni
D016718:Arachidonic Acid / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D030421:Peroxynitrous Acid / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020298:U937 Cells
D030421:Peroxynitrous Acid; D016718:Arachidonic Acid