title: Sphingosine-1-phosphate inhibits IL-1-induced expression of C-C motif ligand 5 via c-Fos-dependent suppression of IFN-β amplification loop.
abstract: The neuroinflammation associated with multiple sclerosis involves activation of astrocytes that secrete and respond to inflammatory mediators such as IL-1. IL-1 stimulates expression of many chemokines, including C-C motif ligand (CCL) 5, that recruit immune cells, but it also stimulates sphingosine kinase-1, an enzyme that generates sphingosine-1-phosphate (S1P), a bioactive lipid mediator essential for inflammation. We found that whereas S1P promotes IL-1-induced expression of IL-6, it inhibits IL-1-induced CCL5 expression in astrocytes. This inhibition is mediated by the S1P receptor (S1PR)-2 via an inhibitory G-dependent mechanism. Consistent with this surprising finding, infiltration of macrophages into sites of inflammation increased significantly in S1PR2(-/-) animals. However, activation of NF-κB, IFN regulatory factor-1, and MAPKs, all of which regulate CCL5 expression in response to IL-1, was not diminished by the S1P in astrocytes. Instead, S1PR2 stimulated inositol 1,4,5-trisphosphate-dependent Ca(++) release and Elk-1 phosphorylation and enhanced c-Fos expression. In our study, IL-1 induced the IFNβ production that supports CCL5 expression. An intriguing finding was that S1P induced c-Fos-inhibited CCL5 directly and also indirectly through inhibition of the IFN-β amplification loop. We propose that in addition to S1PR1, which promotes inflammation, S1PR2 mediates opposing inhibitory functions that limit CCL5 expression and diminish the recruitment of immune cells.
authors.affiliation: *Department of Biochemistry and Molecular Biology, Department of Physiology and Biophysics, and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Jessie W
authors.initials: JW
authors.lastname: Yester
authors.affiliation: *Department of Biochemistry and Molecular Biology, Department of Physiology and Biophysics, and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Bryan
authors.affiliation: *Department of Biochemistry and Molecular Biology, Department of Physiology and Biophysics, and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Waters
authors.affiliation: *Department of Biochemistry and Molecular Biology, Department of Physiology and Biophysics, and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Mierzenski
authors.affiliation: *Department of Biochemistry and Molecular Biology, Department of Physiology and Biophysics, and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Debolina D
authors.initials: DD
authors.lastname: Biswas
authors.affiliation: *Department of Biochemistry and Molecular Biology, Department of Physiology and Biophysics, and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Angela S
authors.initials: AS
authors.lastname: Gupta
authors.affiliation: *Department of Biochemistry and Molecular Biology, Department of Physiology and Biophysics, and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Reetika
authors.initials: R
authors.lastname: Bhardwaj
authors.affiliation: *Department of Biochemistry and Molecular Biology, Department of Physiology and Biophysics, and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Surace
authors.affiliation: *Department of Biochemistry and Molecular Biology, Department of Physiology and Biophysics, and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Eltit
authors.affiliation: *Department of Biochemistry and Molecular Biology, Department of Physiology and Biophysics, and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Sheldon
authors.initials: S
authors.lastname: Milstien
authors.affiliation: *Department of Biochemistry and Molecular Biology, Department of Physiology and Biophysics, and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
authors.affiliation: *Department of Biochemistry and Molecular Biology, Department of Physiology and Biophysics, and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA tkordula@vcu.edu.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kordula
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis; D016899:Interferon-beta / Q000096:biosynthesis / Q000378:metabolism*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D008024:Ligands; D008246:Lysophospholipids / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000502:physiology
chemical_list: C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D007375:Interleukin-1; D008024:Ligands; D008246:Lysophospholipids; D016760:Proto-Oncogene Proteins c-fos; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; C060506:sphingosine 1-phosphate; D016899:Interferon-beta; D011494:Protein Kinases; D013110:Sphingosine
keywords: GPCR; astrocytes; chemokines; inflammation