Toxicity of human monocytic THP-1 cells and microglia toward SH-SY5Y neuroblastoma cells is reduced by inhibitors of 5-lipoxygenase and its activating protein FLAP.
To explore whether the proinflammatory products of the 5-lipoxygenase (5-LOX) pathway are involved in microglia-mediated toxicity toward neuronal cells, we evaluated the effects of 5-LOX inhibitors using an in vitro assay system where human neuronal SH-SY5Y cells are exposed to toxic secretions from THP-1 monocytic cells or human microglia. The specific 5-LOX inhibitors, REV 5901, zileuton, and 5-hydroxyeicosatetraenoic acid lactone; the nonselective LOX inhibitors, phenidone and dapsone; the dual 5-LOX/cyclooxygenase inhibitor, tepoxalin; and the selective inhibitor of the 5-LOX-activating protein (FLAP), MK-886, inhibited such toxicity. The toxicity was enhanced by the 5-LOX product leukotriene (LT)D(4) and reduced by the selective cysteinyl LT receptor (CysLT(1)) antagonist MK-571. The mRNAs for 5-LOX and FLAP were detected in THP-1 cells and human microglia but not in SH-SY5Y cells. The data suggest that inhibition of proinflammatory LT production by 5-LOX inhibition could selectively reduce toxicity of microglial cells and thus be beneficial in neuroinflammatory diseases.
Klegeris
Andis
A
Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, Canada. aklegeri@interchange.ubc.ca
McGeer
Patrick L
PL
D058927:5-Lipoxygenase-Activating Proteins; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D017998:Leukotriene D4 / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017628:Microglia / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology*; D009474:Neurons / Q000166:cytology; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D012333:RNA, Messenger; D017998:Leukotriene D4; D001094:Arachidonate 5-Lipoxygenase