title: Activated protein C decreases tumor necrosis factor related apoptosis-inducing ligand by an EPCR- independent mechanism involving Egr-1/Erk-1/2 activation.
abstract: Background- APC is an antithrombotic and antiinflammatory serine protease that plays an important role in vascular function. We report that APC can suppress the proapoptotic mediator TRAIL in human umbilical vein endothelial cells, and we have investigated the signaling mechanism.
  
  
  RESULTS
  APC inhibited endothelial TRAIL expression and secretion and its induction by cell activation. To explore the mechanism, we examined factors associated with TRAIL regulation and demonstrated that APC increased the level of EGR-1, a transcriptional factor known to suppress the TRAIL promoter. APC also induced a significant increase in phosphorylation of ERK-1/2, required to activate EGR-1 expression. Activation of ERK-1/2 was dependent on the protease activated receptor-1 (PAR-1), but independent of the endothelial protein C receptor (EPCR). Using siRNA, we found that the effect of APC on the EGR-1/ERK signaling required for TRAIL inhibition was dependent on the S1P1 receptor and S1P1 kinase.
  
  
  CONCLUSIONS
  Our data suggest that APC may provide cytoprotective activity by activating the ERK pathway, which upregulates EGR-1 thereby suppressing the expression of TRAIL. Moreover, we provide evidence that APC can induce a cell signaling response through a PAR-1/S1P1-dependent but EPCR-independent mechanism.
authors.affiliation: Biotechnology Discovery Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: Lee A
authors.initials: LA
authors.lastname: O'Brien
authors.forename: Mark A
authors.initials: MA
authors.lastname: Richardson
authors.forename: Sean F
authors.initials: SF
authors.lastname: Mehrbod
authors.forename: David T
authors.initials: DT
authors.lastname: Berg
authors.forename: Bruce
authors.initials: B
authors.lastname: Gerlitz
authors.forename: Akanksha
authors.initials: A
authors.lastname: Gupta
authors.forename: Brian W
authors.initials: BW
authors.lastname: Grinnell
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D019610:Cytoprotection; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism*; D000074283:Endothelial Protein C Receptor; D004789:Enzyme Activation; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D011486:Protein C / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D015703:Antigens, CD; D051766:Early Growth Response Protein 1; D000074283:Endothelial Protein C Receptor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017853:Phosphotransferases (Alcohol Group Acceptor); D011486:Protein C; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface; D049349:Receptors, Lysosphingolipid; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C497325:EGR1 protein, human; C478370:PROCR protein, human; C505653:TNFSF10 protein, human