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

Journal of Leukocyte Biology

Andis Klegeris¹  Patrick L. McGeer¹ 

[1] Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, CanadaKinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, CanadaKinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, Canada

关键词: Alzheimer’s disease;    cytokines;    leukotrienes;    neurodegeneration;    neuroinflammation;    neurotoxicity;   

DOI  :  10.1189/jlb.1002482

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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)D4 and reduced by the selective cysteinyl LT receptor (CysLT1) 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.

【 授权许可】

Unknown