PMID- 21092233
OWN - NLM
STAT- MEDLINE
DCOM- 20110215
LR  - 20220317
IS  - 1471-2121 (Electronic)
IS  - 1471-2121 (Linking)
VI  - 11
DP  - 2010 Nov 23
TI  - The role of HIF-1 in up-regulating MICA expression on human renal proximal 
      tubular epithelial cells during hypoxia/reoxygenation.
PG  - 91
LID - 10.1186/1471-2121-11-91 [doi]
AB  - BACKGROUND: Human 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. RESULTS: We 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. CONCLUSIONS: These 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.
FAU - Luo, Lei
AU  - Luo L
AD  - Key Laboratory of Transplant Engineering and Immunology of Health Ministry of 
      China.
FAU - Lu, Jun
AU  - Lu J
FAU - Wei, Liang
AU  - Wei L
FAU - Long, Dan
AU  - Long D
FAU - Guo, Jia Y
AU  - Guo JY
FAU - Shan, Juan
AU  - Shan J
FAU - Li, Fu S
AU  - Li FS
FAU - Lu, Ping Y
AU  - Lu PY
FAU - Li, Ping Y
AU  - Li PY
FAU - Feng, Li
AU  - Feng L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101123
PL  - England
TA  - BMC Cell Biol
JT  - BMC cell biology
JID - 100966972
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (MHC class I-related chain A)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
SB  - IM
MH  - Cell Hypoxia
MH  - Epithelial Cells/*metabolism
MH  - Heme Oxygenase-1/metabolism
MH  - Histocompatibility Antigens Class I/*metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism/*physiology
MH  - Interferon-gamma/metabolism
MH  - Kidney Tubules, Proximal/*cytology/metabolism
MH  - Killer Cells, Natural/immunology/metabolism
MH  - RNA Interference
MH  - Up-Regulation
MH  - Vascular Endothelial Growth Factor A/metabolism
PMC - PMC3000391
EDAT- 2010/11/26 06:00
MHDA- 2011/02/16 06:00
PMCR- 2010/11/23
CRDT- 2010/11/25 06:00
PHST- 2009/09/04 00:00 [received]
PHST- 2010/11/23 00:00 [accepted]
PHST- 2010/11/25 06:00 [entrez]
PHST- 2010/11/26 06:00 [pubmed]
PHST- 2011/02/16 06:00 [medline]
PHST- 2010/11/23 00:00 [pmc-release]
AID - 1471-2121-11-91 [pii]
AID - 10.1186/1471-2121-11-91 [doi]
PST - epublish
SO  - BMC Cell Biol. 2010 Nov 23;11:91. doi: 10.1186/1471-2121-11-91.