OR17 Heme oxygenase-1 modulates HLA class I antibody-dependent endothelial cell activation

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• 作者：Eva Zilian¹ ; Hendry Saragih¹ ; Oliver Hiller¹ ; Abid Aljabri¹ ; Constanca Figueiredo¹ ; Rainer Blasczyk¹ ; Gregor Theilmeier¹ ; Jan Ulrich Becker² ; Jan Larmann¹ ; Stephan Immenschuh¹
• 刊名：Human Immunology
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：76
• 期：supp_S
• 页码：15
• 全文大小：31 K

文摘

Antibody-mediated rejection (AMR) is a key limiting factor for long-term graft survival in heart and kidney transplantation. Activation of endothelial cells (ECs) via complement-independent effects of human leukocyte antigen class I (HLA I) antibodies (Abs) plays a major role in the pathogenesis of AMR. As the antioxidant enzyme heme oxygenase (HO)-1 is known to have cell type-specific anti-inflammatory effects in the endothelium, we investigated its role on HLA I Ab-dependent activation of human ECs.

Methods

Regulation of inducible proinflammatory endothelial adhesion molecules and chemokines (VCAM-1, ICAM-1, IL-8 and MCP-1) by monoclonal pan- and allele-specific HLA I Abs was determined in cell cultures of primary human umbilical venous, aortic macrovascular and microvascular ECs. HO-1 was modulated by pharmacological regulators and siRNA-mediated knockdown. Adherence of THP-1 monocytes to ECs was determined by leukocyte adhesion assay.

Results

Exposure of human macro- and microvascular EC cultures to HLA I Abs caused endothelial activation, as indicated by up-regulation of VCAM-1, ICAM-1, MCP-1 and IL-8. This up-regulation was mediated via the phosphatidylinositol-3 kinase (PI3K)/Akt and NF-κ$\kappa$B pathways. 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 EC activation. Binding of THP-1 monocytes was enhanced in HLA I Ab-stimulated ECs. This effect was counteracted by HO 1 up-regulation.

Conclusion

HLA I Ab-dependent EC activation is modulated by specific HO-1 up-regulation. Thus, targeted regulation of endothelial HO-1 may be a novel therapeutic approach for the treatment of AMR in kidney and heart transplantation.

S. Immenschuh:Grant/Research Support; Company/Organization; Else Kröner-Fresenius Stiftung EKFS 2012_A309.