Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that regulates a diverse range of physiological processes such as lymphocyte trafficking, cardiac function, vascular development, and inflammation. S1P receptor 1 (S1PR1) agonists possess immunomodulatory/immunosuppresant actions. The S1PR1 agonists fingolimod (FTY720) (Chun & Hartung 2010) and siponimod (BAF312) (Pan et al. 2013, Glaenzel et al. 2018) are effective immunology modulators which are widely used in the treatment of multiple sclerosis.

Fingolimod is being investigated in the management of inflammation caused by COVID-19 (Phase 2 study NCT04280588).

The human gene EDG1 encodes S1PR1 which binds sphingosine 1-phosphate (S1P), a second messenger implicated in cell survival, cell migration, and inflammation (Hla & Maciag 1990). S1PR1 seems to couple with Gi proteins (Lee et al. 1996).

Signal transducer and activator of transcription 3 (STAT3) is a key regulator of gene expression in response to signaling of many cytokines including interleukin-6 (IL6), Oncostatin M, and leukemia inhibitory factor. Using microarray techniques, hundreds of genes have been reported as potential STAT3 target genes (Dauer et al. 2005, Hsieh et al. 2005). Some of these genes have been proven to be direct STAT3 targets using genome-wide chromatin immunoprecipitation screening (Snyder et al. 2008, Carpenter & Lo 2014). Genes for plasma membrane proteins that are upregulated by STAT3 include Intercellular adhesion molecule 1 (ICAM1) (Scuringa et al. 2001), Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B, TNFR2) (Hamilton et al. 2011), Sphingosine 1-phosphate receptor 1 (S1PR1, EDG1) (Lee et al. 2010), Interleukin-6 receptor subunit alpha (IL6R), Interleukin-23 receptor (IL23R) (Durant et al. 2010) and Mucin-1 (MUC1) (Gaemers et al. 2001).

Five EDG-encoded receptors can all bind sphingolipid-1-phosphate (S1P), a second messenger implicated in cell survival, cell migration, and inflammation. The five genes encoding the receptors are EDG1, 3, 5, 6 and 8.
EDG5 encodes the GPCR known as S1PR2 (An S et al, 2000). This protein participates in S1P-induced cell proliferation, survival, and transcriptional activation, effects mediated by coupling to Gi and Gq proteins (Windh RT et al, 1999).
EDG3 encodes a GPCR known as S1PR3 (Yamaguchi F et al, 1996). This protein contributes to the regulation of angiogenesis and vascular endothelial cell function. These effects are mediated by coupling with Gi, Gq/11 and G12/13 proteins (Windh RT et al, 1999).
EDG6 encodes the GPCR known as S1PR4 (Graler MH et al, 1998). This EDG receptor gene is intronless and is specifically expressed in the lymphoid tissue. It's actions are mediated by coupling with Gi/o proteins to inhibit adenylyl cyclase (Van Brocklyn JR et al, 2000).
EDG8 encodes the GPCR known as S1PR5 (Kothapalli R et al, 2002). Its actions are mediated by coupling with Gi/o proteins to inhibit adenylyl cyclase (Im DS et al, 2000).
EDG1 which encodes S1PR1 is annotated in a separte reaction to allow therapeutic interaction.