S1P2 and S1P3 receptor activation promotes fibrotic responses in normal human lung fibroblasts and myofibroblasts

Sphingosine-1-phosphate (S1P) activates a family of 5 different G protein-coupled receptor subtypes, S1P 1-5 receptors, which are involved in a variety of physiological processes. The synthetic, non-selective S1P receptor modulatorFTY-720/ fingolimod(Gilenya®) is the first compound of this class that was approved for treatment of multiple sclerosis. Recently it was shown that the natural ligand S1P and the active phosphorylated metabolite of fingolimod(FTY720-P) induce fibrotic responses in isolated fibroblasts of different tissues (e.g. 1) and fingolimodtreatment caused fibrotic lung changes in rats and monkeys (2). We compared the potential of the non-selective S1P receptor modulators, i.e. S1P and FTY720-P, and the known selective S1P 1 receptor modulators, SEW2871 and ponesimod, to induce fibrotic responses in normal human fibroblasts and myofibroblasts. The non-selective S1P receptor modulatorsS1P and FTY720-P were effective stimulators of fibrotic responses in normal human lung fibroblasts (NHLFs) and myofibroblasts, while the selective S1P 1 receptor modulatorsSEW2871 and ponesimoddisplayed little stimulatory capacity. Both S1P 2 and S1P 3 receptor activation contributed to the pro-fibrotic signal of FTY720-P and the natural agonist S1P in NHLFs. We thus identified S1P 3 and S1P 2 receptors as possible contributors to the pathogenesis of lung fibrosisand as potential novel drug targets.