title: AMP-activated protein kinase as a promoting factor, but complement and thrombin as limiting factors for acquisition of cytoprotection: implications for induction of accommodation.
abstract: Accommodation has been termed as a condition without graft rejection even in the presence of antidonor antibody. We previously reported an in vitro accommodation model, which demonstrated that preincubation of A/B antigen-expressing endothelial cells with anti-A/B antibody resulted in ERK inactivation followed by resistance to complement-mediated cytotoxicity through the induction of complement regulatory genes. However, under the in vivo condition, the effects of complement and coagulation system cannot be ignored. The purpose of this study is to find effective ways to navigate accommodation by exploring the relevant signal transduction. Preincubation with a low level of complement or thrombin failed to induce resistance to complement-mediated cytotoxicity. AMP-activated protein kinase (AMPK) activators such as resveratrol, AICAR and metformin protected endothelial cells against complement-mediated cytotoxicity through the increase in CD55, CD59, haem oxygenase-1 (HO-1) and ferritin heavy chain (ferritin H) genes, all of which were attenuated by AMPKα knock-down. Resveratrol counteracted the inhibitory effect of pretreated complement and thrombin on acquisition of resistance to complement-mediated cytotoxicity through AMPKα. AMPK regulation in endothelial cells could become the potential strategy to induce accommodation in clinical pro-inflammation and pro-coagulation.
authors.affiliation: Department of Transplant Immunology, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Iwasaki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Miwa
authors.forename: Masataka
authors.initials: M
authors.lastname: Haneda
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kuzuya
authors.forename: Haruko
authors.initials: H
authors.lastname: Ogawa
authors.forename: Akira
authors.initials: A
authors.lastname: Onishi
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000494:pharmacology*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives; D018958:CD55 Antigens / Q000096:biosynthesis; D018957:CD59 Antigens / Q000096:biosynthesis; D002460:Cell Line; D003165:Complement System Proteins / Q000276:immunology / Q000633:toxicity*; D019610:Cytoprotection / Q000187:drug effects*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D000077185:Resveratrol; D012265:Ribonucleotides; D015398:Signal Transduction / Q000502:physiology; D013267:Stilbenes / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology*; D014181:Transplantation Immunology
chemical_list: D018958:CD55 Antigens; D018957:CD59 Antigens; D012265:Ribonucleotides; D013267:Stilbenes; C051590:CD59 protein, human; D000620:Aminoimidazole Carboxamide; D003165:Complement System Proteins; D055372:AMP-Activated Protein Kinases; D013917:Thrombin; C031143:AICA ribonucleotide; D000077185:Resveratrol
keywords: AMP-activated protein kinase; accommodation; complement regulatory protein; complement-mediated cytotoxicity; cytoprotective gene; signal transduction pathway