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• W2014799098 abstract "Background and purpose: FTY720 is a potent immunomodulatory prodrug that is converted to its active phosphorylated form by a sphingosine kinase. Here we have studied whether FTY720 mimicked the action of sphingosine‐1‐phosphate (S1P) and exerted an anti‐inflammatory potential in renal mesangial cells. Experimental approach: Prostaglandin E 2 (PGE 2 ) was quantified by an enzyme‐linked immunosorbent‐assay. Secretory phospholipase A 2 (sPLA 2 ) protein was detected by Western blot analyses. mRNA expression was determined by Northern blot analysis and sPLA 2 ‐promoter activity was measured by a luciferase‐reporter‐gene assay. Key results: Stimulation of cells for 24 h with interleukin‐1β (IL‐1β) is known to trigger increased PGE 2 formation which coincides with an induction of the mRNA for group‐IIA‐sPLA 2 and protein expression. FTY720 dose‐dependently suppressed IL‐1β‐induced IIA‐sPLA 2 protein secretion and activity in the supernatant. This effect is due to a suppression of cytokine‐induced sPLA 2 mRNA expression which results from a reduced promoter activity. As a consequence of suppressed sPLA 2 activity, PGE 2 formation is also reduced by FTY720. Mechanistically, the FTY720‐suppressed sPLA 2 expression results from an activation of the TGFβ/Smad signalling cascade since inhibition of the TGFβ receptor type I by a specific kinase inhibitor reverses the FTY720‐mediated decrease of sPLA 2 protein expression and sPLA 2 promoter activity. Conclusions and implications: In summary, our data show that FTY720 was able to mimic the anti‐inflammatory activity of TGFβ and blocked cytokine‐triggered sPLA 2 expression and subsequent PGE 2 formation. Thus, FTY720 may exert additional in vivo effects besides the well reported immunomodulation and its anti‐inflammatory potential should be considered. British Journal of Pharmacology (2007) 150, 943–950. doi: 10.1038/sj.bjp.0707171" @default.
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• W2014799098 date "2007-04-01" @default.
• W2014799098 modified "2023-10-18" @default.
• W2014799098 title "FTY720 suppresses interleukin-1β-induced secretory phospholipase A₂expression in renal mesangial cells by a transcriptional mechanism" @default.
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• W2014799098 doi "https://doi.org/10.1038/sj.bjp.0707171" @default.
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