The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells

Abstract

Protein phosphatase 2A (PP2A) activity can be enhanced pharmacologically by PP2A-activating drugs (PADs). The sphingosine analog FTY720 is the best known PAD and we have shown that FTY720 represses production of pro-inflammatory cytokines responsible for respiratory disease pathogenesis. Whether its phosphorylated form, FTY720-P, also enhances PP2A activity independently of the sphingosine 1-phosphate (S1P) pathway was unknown. Herein, we show that FTY720-P enhances TNF-induced PP2A phosphatase activity and significantly represses TNF-induced interleukin 6 (IL-6) and IL-8 mRNA expression and protein secretion from A549 lung epithelial cells. Comparing FTY720 and FTY720-P with S1P, we show that unlike S1P, the sphingosine analogs do not induce cytokine production on their own. In fact, FTY720 and FTY720-P significantly repress S1P-induced IL-6 and IL-8 production. We then examined their impact on expression of cyclooxygenase 2 (COX-2) and resultant prostaglandin E2 (PGE2) production. S1P did not increase production of this pro-inflammatory enzyme because COX-2 mRNA gene expression is NF-κB-dependent, and unlike TNF, S1P did not activate NF-κB. However, TNF-induced COX-2 mRNA expression and PGE2 secretion is repressed by FTY720 and FTY720-P. Hence, FTY720-P enhances PP2A activity and that PADs can repress production of pro-inflammatory cytokines and enzymes in A549 lung epithelial cells in a manner devoid of S1P agonism.

Mast cells and sphingosine‐1‐phosphate underlie prelesional remodeling in a mouse model of eczema

“…FTY720 treatment prevented enhanced MC degranulation after OVA treatment (Figure A). FTY720 can be phosphorylated in vivo to activate S1PR2 and repress inflammation . FTY720 did not alter skin S1P perhaps because of its inhibitory effect on Sgpl1 that results in S1P increase (Figure B).…”

Protein phosphatase 2A stimulates activation of TFEB and TFE3 transcription factors in response to oxidative stress

“…In vivo, FTY720 is phosphorylated by the enzyme sphingosine kinase 2 to form FTY720-phosphate, which resembles sphingosine 1-phosphate (36). FTY720 and its phosphorylated form have been used to activate PP2A both in vivo and in vitro (37). As seen in Fig.…”

PP2A deactivation is a common event in oral cancer and reactivation by FTY720 shows promising therapeutic potential

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“…Fingolimod (FTY720), is a strong immunosuppressor that has been approved by the US Food and Drug Administration (FDA) to treat relapsed multiple sclerosis (Cohen et al, ). FTY720 possess anticancer activity in multiple myeloma, hepatocellular carcinoma, gastric cancer, ovarian cancer, lung cancer, and colorectal cancer (Hung et al, ; Liao et al, ; Rahman et al, ; Zhang et al, ; Zheng et al, ). Currently it is being uses to treat multiple sclerosis (Montalban et al, ).…”