Secreted phospholipase A _2 group IIA is a neurotoxin released by stimulated human glial cells

摘要

Neuroinflammation, which is one of the hallmarks of neurodegenerative disorders such as Alzheimer's disease, involves secretion of pro-inflammatory mediators by activated glial cells. Secreted phospholipase A _2 group IIA (sPLA _2IIA) has been implicated as an inflammatory mediator contributing to various peripheral inflammatory conditions; however, little is known about the role this enzyme plays in neuroinflammation. Human microglia-like promonocytic THP-1 cells and human primary astrocytes were used to study sPLA _2IIA expression, secretion and function. Production of sPLA _2IIA by these cells was induced in response to stimulation by pro-inflammatory mediators at both mRNA and protein levels. Removal of sPLA _2IIA from stimulated human microglia-like cell and astrocyte supernatants by immunosorbent caused significant reduction of their toxicity towards SH-SY5Y neuroblastoma cells. Both sPLA _2IIA specific and non-specific PLA _2 inhibitors exhibited no anti-cytotoxic or neuroprotective effects, suggesting that sPLA _2IIA cytotoxicity is mediated by a non-enzymatic mechanism. The data obtained indicate that sPLA _2IIA may contribute to the pathogenesis of neurodegenerative diseases involving neuroinflammation. Agents inhibiting the non-enzymatic actions of sPLA _2IIA could be used to slow down progression of neurodegenerative processes that are driven by inflammation.