title: Proton pump inhibitors reduce interferon-γ-induced neurotoxicity and STAT3 phosphorylation of human astrocytes.
abstract: Proton pump inhibitors (PPIs) are known to possess anti-inflammatory properties. Inflammatory processes, including astrocytic activation, are implicated in the pathogenesis of different neurodegenerative diseases. Our recent study has indicated that interferon (IFN)-γ-induced astrocytic neurotoxicity is mediated, at least in part, by phosphorylation of signal transducer and activator of transcription (STAT) 3. We therefore studied the effects of PPIs on IFN-γ-induced neurotoxicity and STAT3 activation of human astrocytes. Both lansoprazole (LPZ) and omeprazole (OPZ) significantly attenuated IFN-γ-induced neurotoxicity of human astrocytes and astrocytoma cells. These drugs inhibited IFN-γ-induced phosphorylation of STAT 3, but not STAT1. We found that LPZ significantly reduced secretion of IFN-γ-inducible T cell α chemoattractant from IFN-γ-activated astrocytes. Neither LPZ nor OPZ suppressed expression of intercellular adhesion molecule-1 by IFN-γ-activated astrocytes. These results suggest that PPIs attenuate IFN-γ-induced neurotoxicity of human astrocytes through inhibition of the STAT3 signaling pathway. PPIs that possess antineurotoxic properties may be a useful treatment option for Alzheimer's disease and other neuroinflammatory disorders associated with activated astrocytes.
authors.affiliation: Department of Psychiatry, The University of British Columbia, Kinsmen Laboratory of Neurological Research, Vancouver, B.C., Canada.
authors.forename: Sadayuki
authors.initials: S
authors.lastname: Hashioka
authors.forename: Andis
authors.initials: A
authors.lastname: Klegeris
authors.forename: Patrick L
authors.initials: PL
authors.lastname: McGeer
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000494:pharmacology*; D000704:Analysis of Variance; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D064747:Lansoprazole; D009853:Omeprazole / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects* / Q000502:physiology; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D054328:Proton Pump Inhibitors; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D064747:Lansoprazole; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D009853:Omeprazole