Conflicts of Interest All authors declare no conflict of interests.
Hypoxia increases membranal and secreted HLA-DR in endothelial cells, rendering them T-cell activators
Article first published online: 2 AUG 2011
© 2011 The Authors. Transplant International © 2011 European Society for Organ Transplantation
Volume 24, Issue 10, pages 1018–1026, October 2011
How to Cite
Lahat, N., Bitterman, H., Weiss-Cerem, L. and Rahat, M. A. (2011), Hypoxia increases membranal and secreted HLA-DR in endothelial cells, rendering them T-cell activators. Transplant International, 24: 1018–1026. doi: 10.1111/j.1432-2277.2011.01304.x
- Issue published online: 6 SEP 2011
- Article first published online: 2 AUG 2011
- Received: 30 March 2011 Revision requested: 10 May 2011 Accepted: 22 June 2011 Published online: 2 August 2011
- endothelial cells;
- graft rejection;
- low oxygen tension
Transplantation involves preoperative ischemic periods that contribute to endothelial cell (EC) dysfunction and T-cell activation, leading to graft rejection. As hypoxia is a major constituent of ischemia, we evaluated its effect on the ability of ECs to express HLA-DR, which is required for presentation of antigens to T cells, and by itself serves as an important target for allogeneic T cells. Primary human umbilical vein ECs (HUVEC) and the human endothelial cell line EaHy926 were incubated in normoxia or hypoxia (PO2 < 0.3%). Hypoxia increased the membranal expression (by 4–6 fold, P < 0.01) and secretion (by sixfold, P < 0.05) of HLA-DR protein, without influencing the accumulation of its mRNA. Alternative splicing, attenuated trafficking, or shedding from the plasma membrane were not observed, but the lysosomal inhibitor bafilomycin A1 reduced HLA-DR secretion. Hypoxia-induced endothelial HLA-DR elevated and diminished the secretion of IL-2 and IL-10, respectively, from co-cultured allogeneic CD4+ T cells in a HLA-DR-dependent manner, as demonstrated by the use of monoclonal anti-HLA-DR. Our results indicate a yet not fully understood post-translational mechanism(s), which elevate both membranal and soluble HLA-DR expression. This elevation is involved in allogeneic T-cell activation, highlighting the pivotal role of ECs in ischemia/hypoxia-associated injury and graft rejection.