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Sphingosine 1-phosphate (S1P), a multi-functional phospholipid mediator, is generated from sphingosine by sphingosine kinases and binds to five known G protein-coupled S1P receptors (S1P 1 , S1P 2 , S1P 3 , S1P 4 , and S1P 5 ). It is widely accepted that S1P receptor 1 (S1P 1 ) plays an essential role in lymphocyte egress from the secondary lymphoid organs (SLO) and thymus, because lymphocyte egress from these organs to periphery is at extremely low levels in mice lacking lymphocytic S1P 1 . Fingolimod hydrochloride (FTY720) is a first-in-class, orally active S1P 1 functional antagonist which was discovered by chemical modification of a natural product, myriocin. Since FTY720 has a structure closely related to sphingosine, the phosphorylated FTY720 (FTY720-P) is converted by sphingosine kinases and binds 4 types of S1P receptors. FTY720-P strongly induces down-regulation of S1P 1 by internalization and degradation of this receptor and acts as a functional antagonist at S1P 1 . Consequently, FTY720 inhibits S1P 1 -dependent lymphocyte egress from the SLO and thymus to reduce circulating lymphocytes including autoreactive Th17 cells, and is highly effective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In relapsing remitting MS patients, oral FTY720 shows a superior efficacy when compared to intramuscular interferon-β-1a. Based on these data, it is presumed that modulation of the S1P-S1P 1 axis provides an effective therapy for autoimmune diseases including MS.

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Role of sphingosine 1-phosphate (S1P) and effects of fingolimod, an S1P receptor 1 functional antagonist in lymphocyte circulation and autoimmune diseases