The role of HIF-1 in up-regulating MICA expression on human renal proximal tubular epithelial cells during hypoxia/reoxygenation

BMC Cell Biology

Research Article

Liang Wei¹  Fu S Li¹  Jia Y Guo¹  Jun Lu¹  Dan Long¹  Juan Shan¹  Li Feng¹  Ping Y Li²  Lei Luo³  Ping Y Lu⁴ 

[1] Key Laboratory of Transplant Engineering and Immunology of Health Ministry of China, China;Key Laboratory of Transplant Engineering and Immunology of Health Ministry of China, China;Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University (No.37 Guo Xue Xiang), 610041, Chengdu, China;Key Laboratory of Transplant Engineering and Immunology of Health Ministry of China, China;Institute of Clinical Medicine, West China Hospital, Sichuan University (No.37 Guo Xue Xiang), 610041, Chengdu, China;Transplantation Institute, West China Hospital, Sichuan University (No.37 Guo Xue Xiang), 610041, Chengdu, China;

关键词: Vascular Endothelial Growth Factor;    Natural Killer Cell;    Natural Killer Cell Cytotoxicity;    Renal Proximal Tubular Epithelial Cell;    Natural Killer Cell Line;   

DOI  :  10.1186/1471-2121-11-91

 received in 2009-09-04, accepted in 2010-11-23,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundHuman major histocompatibility complex class I-related chain A (MICA) plays a dual role in adaptive and innate immune responses. Increasing evidence demonstrates that MICA is closely correlated with acute and chronic kidney allograft rejection. Therefore, understanding the activation mechanisms of MICA is important in kidney transplantation. We previously demonstrated that ischemia/reperfusion injury (IRI) could up-regulate MICA expression on mouse kidney allografts. Since hypoxia-inducible factor-1 (HIF-1) is the master regulator of cellular adaptive responses to hypoxia during IRI, here we investigate whether HIF-1 could up-regulate MICA expression and its influence on NK cell cytotoxicity.ResultsWe find that HIF-1alpha plays an important role in up-regulating MICA expression, inducing IFNgamma secretion and NK cell cytotoxicity during hypoxia/reoxygenation. First, we generated a HIF-1alphaDELTAODD-expressing adenovirus to stably and functionally express HIF-1alpha in human renal proximal tubular epithelial (HK-2) cells under normoxia conditions. HIF-1alpha over-expression in HK-2 cells induces MICA expression and enhances NK cell cytotoxic activity towards cells that express HIF-1alpha. Second, we used a hypoxia/reoxygenation cell model to simulate IRI in vitro and found that the suppression of HIF-1alpha by RNAi induces down-regulation of MICA expression and inhibits NK cytotoxicity. In antibody blocking experiments, an anti-MICA mAb was able to down-regulate NK cell cytotoxic activity towards HK-2 cells that over-expressed HIF-1alpha. Moreover, when NK cells were co-cultured with the HK-2 cells expressing MICA, which was up-regulated by over-expression of HIF-1alpha, there was a significant increase in the secretion of IFNgamma. In the presence of the blocking MICA mAb, IFNgamma secretion was significantly decreased.ConclusionsThese results demonstrate that hypoxia/reoxygenation-promoted MICA expression on HK-2 cells is through a HIF-1 pathway. The increased IFNgamma secretion and enhanced NK cell cytotoxicity was mainly due to the surface expression of MICA induced by over-expression of HIF-1alpha. This study enhances our understanding of MICA activation mechanisms during kidney transplantation and provides insights into how IRI can influence transplant outcome. Moreover, these findings might be also important for developing strategies to reduce the effect of MICA in kidney transplant outcomes in the future.

【 授权许可】

Unknown   
© Luo et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.