Heme Oxygenase-1 Inhibits HLA Class I Antibody-Dependent Endothelial Cell Activation |
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Authors: | Eva Zilian Hendry Saragih Vijith Vijayan Oliver Hiller Constanca Figueiredo Abid Aljabri Rainer Blasczyk Gregor Theilmeier Jan Ulrich Becker Jan Larmann Stephan Immenschuh |
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Institution: | 1. Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.; 2. Faculty of Biology, Gadjah Mada University, Yogyakarta, Indonesia.; 3. Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.; 4. Institute of Pathology, University Hospital of Cologne, Cologne, Germany.; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, POLAND, |
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Abstract: | Antibody-mediated rejection (AMR) is a key limiting factor for long-term graft survival in solid organ transplantation. Human leukocyte antigen (HLA) class I (HLA I) antibodies (Abs) play a major role in the pathogenesis of AMR via their interactions with HLA molecules on vascular endothelial cells (ECs). The antioxidant enzyme heme oxygenase (HO)-1 has anti-inflammatory functions in the endothelium. As complement-independent effects of HLA I Abs can activate ECs, it was the goal of the current study to investigate the role of HO-1 on activation of human ECs by HLA I Abs. In cell cultures of various primary human macro- and microvascular ECs treatment with monoclonal pan- and allele-specific HLA I Abs up-regulated the expression of inducible proinflammatory adhesion molecules and chemokines (vascular cell adhesion molecule-1 VCAM-1], intercellular cell adhesion molecule-1 ICAM-1], interleukin-8 IL-8] and monocyte chemotactic protein 1 MCP-1]). Pharmacological induction of HO-1 with cobalt-protoporphyrin IX reduced, whereas inhibition of HO-1 with either zinc-protoporphyrin IX or siRNA-mediated knockdown increased HLA I Ab-dependent up-regulation of VCAM-1. Treatment with two carbon monoxide (CO)-releasing molecules, which liberate the gaseous HO product CO, blocked HLA I Ab-dependent EC activation. Finally, in an in vitro adhesion assay exposure of ECs to HLA I Abs led to increased monocyte binding, which was counteracted by up-regulation of HO-1. In conclusion, HLA I Ab-dependent EC activation is modulated by endothelial HO-1 and targeted induction of this enzyme may be a novel therapeutic approach for the treatment of AMR in solid organ transplantation. |
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