Significance of HLA class I antibody-induced antioxidant gene expression for endothelial cell protection against complement attack.
It has been observed that a graft organ continues to survive and function normally even in the presence of anti-graft antibodies. However, the mechanisms behind acquirement of this condition remain unknown. Here we report that the anti-HLA ligation on endothelial cells induces PI3K/AKT activation followed by antioxidant gene induction through Nrf2-mediated antioxidant-responsive element (ARE) activation. Activation of PI3K/AKT in endothelial cells by a low concentration of anti-HLA ligation enhances protection from complement attack. A real-time quantitative PCR and flow-cytometry experiment showed that ferritin H and HO-1 mRNAs were induced in a PI3K/AKT-dependent manner, while CD55 and CD59 expression were not enhanced by anti-HLA ligation. Anti-HLA ligation on endothelial cells activates ferritin H ARE and induces Nrf2 binding on its enhancer element. Finally, overexpression of Nrf2 in endothelial cells attenuates complement-mediated cytotoxicity. These experiments suggest that induction of PI3K/AKT-dependent cytoprotective genes by Nrf2 is an important mechanism to prevent complement attack. Thus, a protocol to activate this pathway would be a potential strategy for avoidance of graft rejection in transplantation.
Iwasaki
Kenta
K
Department of Applied Immunology, Nagoya University School of Medicine, Nagoya, Japan.
Miwa
Yuko
Y
Haneda
Masataka
M
Uchida
Kazuharu
K
Nakao
Akimasa
A
Kobayashi
Takaaki
T
D000906:Antibodies / Q000276:immunology*; D001052:Apoferritins / Q000235:genetics*; D002478:Cells, Cultured; D003167:Complement Activation; D003165:Complement System Proteins / Q000276:immunology*; D019610:Cytoprotection / Q000235:genetics / Q000276:immunology; D042783:Endothelial Cells / Q000201:enzymology / Q000276:immunology*; D015870:Gene Expression; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D051547:Heme Oxygenase-1 / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D000906:Antibodies; D015395:Histocompatibility Antigens Class I; D003165:Complement System Proteins; D001052:Apoferritins; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt