Effect of FTY720-phosphate on the expression of inflammation-associated molecules in astrocytes in vitro.

Abstract

FTY720 is a new oral immunomodulatory therapy for the treatment of multiple sclerosis (MS). There is strong evidence that FTY720 has direct effects on brain resident cells such as astrocytes acting via sphingosine‑1‑phosphate (S1P) receptors. In the present study, the mRNA expression of S1P receptors as well as selected cytokines, chemokines and growth factors were investigated in primary murine astrocytes under inflammatory conditions in the presence or absence of the phosphorylated form of FTY720 (FTY720‑P). Following stimulation with either the pro‑inflammatory cytokine tumor necrosis factor‑α (TNF‑α) or with bacterial lipopolysaccharide, there was an increased expression of the receptors S1P1 and S1P3, the cytokines and chemokines interleukin (IL)‑1β, chemokine (C‑C‑motif) ligand 2 (CCL‑2), CCL‑20 and chemokine (C‑X‑C‑motif) ligand 12 as well as the growth factors insulin‑like growth factor‑1, ciliary neurotrophic factor and glial cell line‑derived neurotrophic factor (GDNF). FTY720‑P led to an increased expression of IL‑1β and GDNF at distinct time points following co‑stimulation with TNF‑α compared with TNF‑α treatment alone. However, the presence of FTY720‑P did not have any further significant effects on the expression of S1P receptors, cytokines or growth factors, suggesting that the regulation of these target genes in astrocytes is not likely to be a major mechanism underlying the effect of FTY720‑P in diseases such as MS.