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 fo...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2010-01, Vol.391 (2), p.1210-1215
Main Authors: Iwasaki, Kenta, Miwa, Yuko, Haneda, Masataka, Uchida, Kazuharu, Nakao, Akimasa, Kobayashi, Takaaki
Format: Article
Language:English
Subjects:
Anti-HLA antibody
Antibodies - immunology
Apoferritins - genetics
Cells, Cultured
Complement Activation
Complement System Proteins - immunology
Cytoprotection
Cytoprotection - genetics
Cytoprotection - immunology
Endothelial Cells - enzymology
Endothelial Cells - immunology
Ferritin
Gene Expression
Graft Rejection - genetics
Graft Rejection - immunology
Graft Rejection - prevention & control
Graft Survival - genetics
Graft Survival - immunology
Heme Oxygenase-1 - genetics
Histocompatibility Antigens Class I - immunology
HO-1
Humans
Nrf2
Phosphatidylinositol 3-Kinases - metabolism
PI3K/AKT
Proto-Oncogene Proteins c-akt - metabolism
Transplantation
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Summary: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.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2009.12.042