title: Secreted phospholipase A(2) group IIA is a neurotoxin released by stimulated human glial cells.
abstract: 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(2)IIA) 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(2)IIA expression, secretion and function. Production of sPLA(2)IIA by these cells was induced in response to stimulation by pro-inflammatory mediators at both mRNA and protein levels. Removal of sPLA(2)IIA from stimulated human microglia-like cell and astrocyte supernatants by immunosorbent caused significant reduction of their toxicity towards SH-SY5Y neuroblastoma cells. Both sPLA(2)IIA specific and non-specific PLA(2) inhibitors exhibited no anti-cytotoxic or neuroprotective effects, suggesting that sPLA(2)IIA cytotoxicity is mediated by a non-enzymatic mechanism. The data obtained indicate that sPLA(2)IIA may contribute to the pathogenesis of neurodegenerative diseases involving neuroinflammation. Agents inhibiting the non-enzymatic actions of sPLA(2)IIA could be used to slow down progression of neurodegenerative processes that are driven by inflammation.
authors.affiliation: Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia Okanagan, Kelowna, BC, Canada.
authors.forename: Erika B
authors.initials: EB
authors.lastname: Villanueva
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Little
authors.forename: Gérard
authors.initials: G
authors.lastname: Lambeau
authors.forename: Andis
authors.initials: A
authors.lastname: Klegeris
mesh_terms: D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D054501:Group II Phospholipases A2 / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D009498:Neurotoxins; D011994:Recombinant Proteins; D054501:Group II Phospholipases A2; C516287:PLA2G2A protein, human