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  • Fingolimod suppresses the proinflammatory status of interferon-[gamma]-activated cultured rat astrocytes
    Trkov, Saša ...
    Astroglia, the primary homeostatic cells of the central nervous system, play an important role in neuroinflammation. They act as facultative immunocompetent antigen-presenting cells (APCs), ... expressing major histocompatibility complex (MHC) class II antigens upon activation with interferon (IFN)-[gamma] and possibly other proinflammatory cytokines that are upregulated in disease states, including multiple sclerosis (MS).We characterized the anti-inflammatory effects of fingolimod (FTY720), an established drug for MS, and its phosphorylated metabolite (FTY720-P) in IFN-[gamma]-activated cultured rat astrocytes. The expression of MHC class II compartments, [beta]2 adrenergic receptor (ADR-[beta]2), and nuclear factor kappa-light-chain enhancer of activated B cells subunit p65 (NF-KB p65) was quantified in immunofluorescence images acquired by laser scanning confocal microscopy. In addition, MHC class II-enriched endocytotic vesicles were labeled by fluorescent dextran and their mobility analyzed in astrocytes subjected to different treatments. FTY720 and FTY720-P treatment significantly reduced the number of IFN-K-induced MHC class II compartments and substantially increased ADR-[beta]2 expression, which is otherwise small or absent in astrocytes in MS. These effects could be partially attributed to the observed decrease in NF-KB p65 expression, because the NF-KB signaling cascade is activated in inflammatory processes.We also found attenuated trafficking and secretion from dextran-labeled endo-/lysosomes that may hinder efficient delivery of MHC class II molecules to the plasma membrane. Our data suggest that FTY720 and FTY720-P at submicromolar concentrations mediate anti-inflammatory effects on astrocytes by suppressing their action as APCs, which may further downregulate the inflammatory process in the brain, constituting the therapeutic effect of fingolimod in MS.
    Vir: Molecular neurobiology. - ISSN 0893-7648 (Vol. 56, iss. 9, Sep. 2019, str. 5971-5986)
    Vrsta gradiva - članek, sestavni del
    Leto - 2019
    Jezik - angleški
    COBISS.SI-ID - 34175449

    Povezava(-e):

    https://link.springer.com/article/10.1007%2Fs12035-019-1481-x
    DOI

vir: Molecular neurobiology. - ISSN 0893-7648 (Vol. 56, iss. 9, Sep. 2019, str. 5971-5986)
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