Sodium dependence of lysophosphatidylcholine-induced caspase-1 activity and reactive oxygen species generation.
The proinflammatory cytokines interleukin (IL)-1β and IL-18 play pivotal roles in neuroinflammatory diseases. Caspase-1-mediated proteolytic cleavage is required to convert the premature, biologically inactive cytokines to their biologically active forms capable of promoting tissue inflammation. Although caspases have been recognized as potential therapeutic targets in inflammatory diseases, mechanisms regulating caspase-1 activation are not fully understood. Here we demonstrate that the proinflammatory lipid lysophosphatidylcholine (LPC) initiates microglial caspase-1 activation in a Na(+)-dependent manner. LPC-induced caspase-1 activity was almost completely inhibited upon omission of extracellular Na(+), but was unaffected by inhibition of Na(+)/K(+)-ATPase with ouabain or by inhibition of Na(+)/H(+) antiport with amiloride. Inhibition of caspase-1-mediated IL-1β processing by Na(+)-free medium led to reduced amounts of mature IL-1β released from LPC-stimulated microglia. Furthermore, LPC-induced production of reactive oxygen species (ROS) was abolished by Na(+)-free medium, indicating Na(+) dependence of NADPH oxidase activity in LPC-stimulated microglia. Since ROS production was found to be crucial to caspase-1 activation in LPC-stimulated microglia, the Na(+) dependence of caspase-1 can be related to the Na(+) dependence of NADPH oxidase. In summary, it is suggested that in LPC-activated microglia, Na(+) influx is required for the production of NADPH oxidase-mediated ROS, which subsequently stimulate caspase-1 activity.
Schilling
Tom
T
Division of Basic Medical Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
Eder
Claudia
C
D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D003470:Culture Media / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D053583:Interleukin-1beta / Q000378:metabolism*; D008244:Lysophosphatidylcholines / Q000276:immunology / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000276:immunology / Q000378:metabolism*; D015213:Neuroimmunomodulation; D010042:Ouabain / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors
D003470:Culture Media; D053583:Interleukin-1beta; D008244:Lysophosphatidylcholines; D017382:Reactive Oxygen Species; D026941:Sodium Channel Blockers; D010042:Ouabain; D000584:Amiloride; D012964:Sodium; D019255:NADPH Oxidases; D020170:Caspase 1; D000254:Sodium-Potassium-Exchanging ATPase