title: Anti-HLA class I antibody-mediated activation of the PI3K/Akt signaling pathway and induction of Bcl-2 and Bcl-xL expression in endothelial cells.
abstract: Anti-human leukocyte antigen (HLA) antibodies (Ab) have long been implicated in the process of acute and chronic allograft rejection, yet their mechanism(s) of action is not well understood. The aim of this study was to determine whether ligation of HLA class I molecules by anti-HLA Ab on the surface of human endothelial cells (EC) activates the PI3 Kinase (PI3K)/Akt signaling pathway and downstream target proteins of the cell death apparatus. We report that Ab ligation of major histocompatibility complex (MHC) class I molecules on the surface of EC triggers phosphorylation of Akt, PI3K, and recruitment of PI3K and Akt into a signaling unit with focal adhesion kinase. Signaling through class I also stimulated phosphorylation of Bad and upregulated expression of Bcl-2 and Bcl-xL. Pretreatment of EC with the PI3K inhibitor wortmannin blocked class I-mediated expression of Bcl-2, but not Bcl-xL, suggesting a role for the PI3K/Akt signaling pathway in regulation of class I-induced Bcl-2 expression. The intracellular events initiated by class I ligation were influenced by the concentration of the anti-HLA Ab with the lowest tested concentrations of Ab stimulating the highest level of Akt phosphorylation, Bcl-xL and Bcl-2 expression. Consistent with the in vitro experiments, analysis of biopsy samples from heart transplant recipients with evidence of Ab-mediated rejection exhibited increased Bcl-2 expression on the vascular endothelium. These results suggest that exposure of the graft endothelium to low concentrations of anti-HLA Ab may promote cell survival by transducing signals resulting in upregulation of cell survival genes.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Jin
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Said
authors.forename: Peter T
authors.initials: PT
authors.lastname: Jindra
authors.forename: Raja
authors.initials: R
authors.lastname: Rajalingam
authors.forename: Enrique
authors.initials: E
authors.lastname: Rozengurt
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Reed
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000906:Antibodies / Q000276:immunology*; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006680:HLA Antigens / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D015854:Up-Regulation / Q000235:genetics; D000077191:Wortmannin; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000730:Androstadienes; D000906:Antibodies; D002352:Carrier Proteins; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D000077191:Wortmannin; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D019061:src-Family Kinases; C494819:BAD protein, human; C494811:BCL2L1 protein, human; C496050:PTK2 protein, human; C494918:AKT1 protein, human