FTY720 suppresses interleukin -1β -induced secretory phospholipase A2 expression in renal mesangial cells by a transcriptional mechanism

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 E2 (PGE2) was quantified by an enzyme-linked immunosorbent-assay. Secretory phospholipase A2 (sPLA2) protein was detected by Western blot analyses. mRNA expression was determined by Northern blot analysis and sPLA2-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 PGE2 formation which coincides with an induction of the mRNA for group-IIA-sPLA2 and protein expression. FTY720 dose-dependently suppressed IL-1β-induced IIA-sPLA2 protein secretion and activity in the supernatant. This effect is due to a suppression of cytokine-induced sPLA2 mRNA expression which results from a reduced promoter activity. As a consequence of suppressed sPLA2 activity, PGE2 formation is also reduced by FTY720. Mechanistically, the FTY720-suppressed sPLA2 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 sPLA2 protein expression and sPLA2 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 sPLA2 expression and subsequent PGE2 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