Abstract
We report that potassium leakage from cells leads to activation of the Ca2+-independent phospholipase A2 (iPLA2), and the latter plays a pivotal role in regulating the cleavage of pro-IL-1 beta by the IL-converting enzyme caspase-1 in human monocytes. K+ efflux led to increases of cellular levels of glycerophosphocholine, an unambiguous indicator of phospholipase A2 activation. Both maturation of IL-1 beta and formation of glycerophosphocholine were blocked by bromoenol lactone, the specific iPLA2 inhibitor. Bromoenol lactone-dependent inhibition of IL-1 beta processing was not due to perturbation of the export machinery for pro-IL-1 beta and IL-1 beta or to caspase-1 suppression. Conspicuously, activation of Ca2+-dependent phospholipase A2 did not support but rather suppressed IL-1 beta processing. Thus, our findings reveal a specific role for iPLA2 activation in the sequence of events underlying IL-1 beta maturation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Biological Transport / drug effects
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Biological Transport / immunology
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Calcium / metabolism
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Calcium / physiology*
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Caspase 1 / metabolism
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Caspase Inhibitors
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Cells, Cultured
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Enzyme Activation / drug effects
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Enzyme Activation / immunology
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Humans
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Immunosuppressive Agents / pharmacology
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Interleukin-1 / antagonists & inhibitors
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Interleukin-1 / metabolism*
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Intracellular Fluid / enzymology
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Intracellular Fluid / immunology
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Intracellular Fluid / metabolism
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Monocytes / drug effects
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Monocytes / enzymology
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Monocytes / immunology
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Monocytes / metabolism
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Naphthalenes / pharmacology
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Phospholipases A / antagonists & inhibitors
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Phospholipases A / physiology*
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Phospholipases A2
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Potassium / metabolism
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Potassium / physiology*
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Protein Processing, Post-Translational / immunology*
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Pyrones / pharmacology
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Caspase Inhibitors
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Immunosuppressive Agents
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Interleukin-1
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Naphthalenes
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Pyrones
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Tumor Necrosis Factor-alpha
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6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one
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Phospholipases A
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Phospholipases A2
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Caspase 1
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Potassium
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Calcium