title: Everolimus inhibits anti-HLA I antibody-mediated endothelial cell signaling, migration and proliferation more potently than sirolimus.
abstract: Antibody (Ab) crosslinking of HLA I molecules on the surface of endothelial cells triggers proliferative and pro-survival intracellular signaling, which is implicated in the process of chronic allograft rejection, also known as transplant vasculopathy (TV). The purpose of this study was to investigate the role of mammalian target of rapamycin (mTOR) in HLA I Ab-induced signaling cascades. Everolimus provides a tool to establish how the mTOR signal network regulates HLA I-mediated migration, proliferation and survival. We found that everolimus inhibits mTOR complex 1 (mTORC1) by disassociating Raptor from mTOR, thereby preventing class I-induced phosphorylation of mTOR, p70S6K, S6RP and 4E-BP1, and resultant class I-stimulated cell migration and proliferation. Furthermore, we found that everolimus inhibits class I-mediated mTORC2 activation (1) by disassociating Rictor and Sin1 from mTOR; (2) by preventing class I-stimulated Akt phosphorylation and (3) by preventing class I-mediated ERK phosphorylation. These results suggest that everolimus is more effective than sirolimus at antagonizing both mTORC1 and mTORC2, the latter of which is critical in endothelial cell functional changes leading to TV in solid organ transplantation after HLA I crosslinking. Our findings point to a potential therapeutic effect of everolimus in prevention of chronic Ab-mediated rejection.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA.
authors.forename: Y-P
authors.initials: YP
authors.lastname: Jin
authors.forename: N M
authors.initials: NM
authors.lastname: Valenzuela
authors.forename: M E
authors.initials: ME
authors.lastname: Ziegler
authors.forename: E
authors.initials: E
authors.lastname: Rozengurt
authors.forename: E F
authors.initials: EF
authors.lastname: Reed
mesh_terms: D000906:Antibodies / Q000276:immunology / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D000068338:Everolimus; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D047468:Immunoprecipitation; D007166:Immunosuppressive Agents / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014945:Wound Healing
chemical_list: D000906:Antibodies; D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D046912:Multiprotein Complexes; D000068338:Everolimus; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Endothelial cells; HLA; everolimus; mTOR; signal transduction; transplantation