Sphingosine-1-phosphate inhibits IL-1-induced expression of C-C motif ligand 5 via c-Fos-dependent suppression of IFN-β amplification loop.
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.
['Yester|Jessie W|JW|', 'Bryan|Lauren|L|', 'Waters|Michael R|MR|', 'Mierzenski|Bartosz|B|', 'Biswas|Debolina D|DD|', 'Gupta|Angela S|AS|', 'Bhardwaj|Reetika|R|', 'Surace|Michael J|MJ|', 'Eltit|Jose M|JM|', 'Milstien|Sheldon|S|', 'Spiegel|Sarah|S|', 'Kordula|Tomasz|T|']
D000818:Animals D002478:Cells, Cultured D018946:Chemokine CCL5 D006801:Humans D050856:Interferon Regulatory Factor-1 D016899:Interferon-beta D007375:Interleukin-1 D008024:Ligands D008246:Lysophospholipids D051379:Mice D018345:Mice, Knockout D010766:Phosphorylation D011494:Protein Kinases D016760:Proto-Oncogene Proteins c-fos D050794:STAT1 Transcription Factor D050795:STAT2 Transcription Factor D013110:Sphingosine
astrocytes chemokines inflammation GPCR