| Author/Editor | Trkov, Saša; Stenovec, Matjaž; Miš, Katarina; Pirkmajer, Sergej; Zorec, Robert | |
| Title | Fingolimod suppresses the proinflammatory status of interferon-[gamma]-activated cultured rat astrocytes | |
| Type | članek | |
| Publication year | 2019 | |
| Volume | str. str. | |
| ISSN | 0893-7648 - Molecular neurobiology | |
| Language | eng | |
| Abstract | 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. | |
| Keywords | astrociti centralni živčni sistem interferon-gama astrocytes central nervous system interferon-gamma |