Monocytic cell necrosis is mediated by potassium depletion and caspase-like proteases

Apoptosis is a physiological cell death that culminates in mitochondrial pe rmeability transition and the activation of caspases, a family of cysteine proteases. Necrosis, in contrast, is a pathological cell death characterize d by swelling of the cytoplasm and mitochondria and rapid plasma membrane d isruption. Necrotic cell death has long been opposed to apoptosis, but it n ow appears that both pathways involve mitochondrial permeability transition , raising the question of what mediates necrotic cell death. In this study, we investigated mechanisms that promote necrosis induced by various stimul i (Clostridium difficile toxins, Staphylococcus aureus alpha toxin, ouabain , nigericin) in THP-1 cells, a human monocytic cell line, and in monocytes. All stimuli induced typical features of necrosis and triggered protease-me diated release of interleukin-1 beta (IL-1 beta) and CD14 in both cell type s. K+ depletion was actively implicated in necrosis because substituting K for Na+ in the extracellular medium prevented morphological features of ne crosis and IL-1 beta release. N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a broad-spectrum caspase inhibitor, prevented morphological feature s of necrosis, plasma membrane destruction, loss of mitochondrial membrane potential, IL-1 beta release, and CD14 shedding induced by all stimuli. Thu s, in monocytic cells, necrosis is a cell death pathway mediated by passive K+ efflux and activation of caspase-like proteases.