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• W2794429897 abstract "Abstract Sphingosine 1‐phosphate receptors (S1 PR ) are G protein‐coupled and compose a family with five subtypes, S1P1R–S1P5R. The drug Gilenya ® (Novartis, Basel, Switzerland) (Fingolimod; FTY 720) targets S1 PR s and was the first oral therapy for patients with relapsing‐remitting multiple sclerosis ( MS ). The phosphorylated form of FTY 720 ( pFTY 720) binds S1 PR s causing initial agonism, then subsequent receptor internalization and functional antagonism. Internalization of S1P1R attenuates sphingosine 1‐phosphate (S1P)‐mediated egress of lymphocytes from lymph nodes, limiting aberrant immune function in MS . pFTY 720 also exerts direct actions on neurons and glial cells which express S1 PR s. In this study, we investigated the regulation of pro‐inflammatory chemokine release by S1 PR s in enriched astrocytes and microglial cultures. Astrocytes and microglia were stimulated with lipopolysaccharide ( LPS ) and increases in C‐X‐C motif chemokine 5 ( CXCL 5), also known as LIX (lipopolysaccharide‐induced CXC chemokine) expression were quantified. Results showed that pFTY 720 attenuated LPS ‐induced CXCL 5 ( LIX ) protein release from astrocytes, as did the S1P1R selective agonist, SEW 2871. In addition, pFTY 720 blocked messenger ribonucleic acid ( mRNA ) transcription of the chemokines, (i) CXCL 5/ LIX , (ii) C‐X‐C motif chemokine 10 ( CXCL 10) also known as interferon gamma‐induced protein 10 ( IP 10) and (iii) chemokine (C‐C motif) ligand 2 ( CCL 2) also known as monocyte chemoattractant protein 1 ( MCP 1). Interestingly, inhibition of sphingosine kinase attenuated LPS ‐induced increases in mRNA levels of all three chemokines, suggesting that LPS ‐ TLR 4 (Toll‐like receptor 4) signalling may enhance chemokine expression via S1P‐S1 PR transactivation. Lastly, these observations were not limited to astrocytes since we also found that pFTY 720 attenuated LPS ‐induced release of CXCL 5 from microglia. These data highlight a role for S1 PR signalling in regulating the levels of chemokines in glial cells and support the notion that pFTY 720 efficacy in multiple sclerosis may involve the direct modulation of astrocytes and microglia. image" @default.
• W2794429897 created "2018-03-29" @default.
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• W2794429897 date "2018-02-21" @default.
• W2794429897 modified "2023-10-14" @default.
• W2794429897 title "Sphingosine 1‐phosphate receptors regulate <scp>TLR</scp>4‐induced <scp>CXCL</scp>5 release from astrocytes and microglia" @default.
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• W2794429897 doi "https://doi.org/10.1111/jnc.14313" @default.
• W2794429897 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/29377126" @default.
• W2794429897 hasPublicationYear "2018" @default.
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