Sphingosine-1-phosphate (S1P), the bioactive product of sphingosine kinase (SK) activation, is a survival factor for endothelial cells. The mechanism of SK-mediated survival was investigated in endothelial cells with moderately raised intracellular SK activity. Overexpression of SK mediated survival primarily through the activation of the phosphatidyl inositol 3-kinase (PI-3K)/protein kinase B (Akt/PKB) pathway and an associated up-regulation of the antiapoptotic protein B cell lymphoma gene 2 (Bcl-2) and down-regulation of the proapoptotic protein bisindolylmaleimide (Bcl-2 interacting mediator of cell death; Bim). In addition there was an up-regulation and dephosphorylation of the junctional molecule platelet endothelial cell adhesion molecule-1 (PECAM-1), which was obligatory for activation of the PI-3K/Akt pathway, for SK-induced cell survival, and for the changes in the apoptosis-related proteins. Thus, raised intracellular SK activity induced a molecule involved in cell-cell interactions to augment cell survival through a PI-3K/Akt-dependent pathway. This is distinct from the activation of both PI-3K/Akt and mitogen-activated pro- IntroductionEndothelial cell (EC) survival is regulated by cell-matrix and cell-cell interactions and by growth factors. Cell-matrix attachments are mediated by the integrins, and integrin ligation triggers downstream signaling events that inhibit apoptosis or anoikis. 1,2 Two cell-cell adhesion molecules are critical in the control of endothelial cell survival. The junctional molecule platelet endothelial cell adhesion molecule-1 (PECAM-1; CD31), a 130-kDa member of the immunoglobulin-immunoreceptor tyrosine-based inhibitory motif (Ig-ITIM) family of inhibitory receptors, possesses a functional cytoplasmic ITIM domain, is constitutively and abundantly expressed on normal endothelium 3 regulating leukocyte transmigration 4 and acts as a structural protein in cell-cell attachments. PECAM-1 is also able to suppress programmed cell death 5-9 by virtue of homophilic interactions. VE-cadherin, an endothelial-specific major structural protein involved in adherens junctions, is also involved in mediating the antiapoptotic effects of vascular endothelial cell growth factor 10 (VEGF). VEGF and basic fibroblast growth factor (bFGF) prevent EC apoptosis through activation of the phosphatidyl inositol 3-kinase (PI-3K)/protein kinase B (Akt/PKB) pathway and the Raf/MEK/MAPK (relative activity factor/mitogen-induced extracellular kinase/mitogenactivated protein kinase) pathway, both of which are critical pathways promoting cell survival. [11][12][13][14][15][16] Serum is also a recognized trophic factor for ECs since they undergo apoptosis within 24 hours of serum deprivation. 16 The protective factors in serum have been attributed to lysophosphatidic acid, sphingosine-1-phosphate (S1P), [17][18][19] and high-density lipoproteins. 20 The lipid mediator S1P is formed by the phosphorylation of membrane-associated sphingosine by sphingosine kinase (SK). S1P is stored in high concentrations in th...

The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of rare autoimmune diseases characterized by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2,566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of dermatomyositis (DM, n=879), juvenile dermatomyositis (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (IBM, n=252) patients collected from 14 countries through the Myositis Genetics Consortium. The human leukocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10−8). Nine regions were associated at a significance level of p<2.25×10−5, including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM, and JDM. This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.