Progesterone Induces Human Leukocyte Antigen-G Expression in Vascular Endothelial and Smooth Muscle Cells

Abstract

Background-Human leukocyte antigen-G (HLA-G) expression in heart transplant patients has been negatively associated with acute cellular rejection and cardiac allograft vasculopathy. We assessed HLA-G expression in vascular human endothelial and smooth muscle cell cultures to determine if future therapeutic agents can be targeted toward inducing HLA-G expression to protect against allograft rejection and vasculopathy. Methods and Results-Human coronary artery endothelial, aortic endothelial, and coronary artery smooth muscle cell cultures were exposed to cytokines (interferon-␥ or interleukin-10), hypoxia/reoxygenation stress, immunosuppressive agents (cyclosporine, sirolimus, or tacrolimus), or progesterone. HLA-G was not expressed by untreated, normoxic cells. Furthermore, maximal doses of interferon-␥, interleukin-10, cyclosporine, sirolimus, or tacrolimus, as well as exposure to hypoxia/reoxygenation, failed to induce HLA-G expression. HLA-G, which has previously not been detected in adult vascular endothelial and smooth muscle cells, was detected by enzyme-linked immunosorbent assay and flow cytometry in human coronary artery endothelial, human coronary aortic endothelial, and human coronary artery smooth muscle cultures after incubation with progesterone in a dose-dependent manner (PϽ0.001) with no change in cellular proliferation ability or viability. This effect was partially blocked in the presence of mifepristone, a progesterone receptor antagonist (human coronary artery endothelial: 48.8Ϯ15.6%; human coronary aortic endothelial: 59.5Ϯ9.5%; human coronary artery smooth muscle: 59.8Ϯ9.8% of control; PϽ0.05). Progesterone-induced HLA-G expression was not protective against hypoxia/reoxygenation injury. Conclusions-HLA-G is not expressed at baseline in vascular endothelial and smooth muscle cells but can be induced by exposure to progesterone. Although tightly regulated, induction of HLA-G expression in these cells may represent a promising and novel therapeutic strategy to protect against rejection and cardiac allograft vasculopathy after heart transplantation.

Everolimus But Not Mycophenolate Mofetil Therapy Is Associated With Soluble HLA-G Expression in Heart Transplant Patients

“…Interestingly, cell-surface and circulating HLA-G isoforms have also shown to be protective through inhibition of immune responses directed against the allograft endothelium. We have recently shown that HLA-G can be upregulated in human endothelium cells in vitro, 36 which might represent a strategy to protect against immune-mediated endothelial damage post-transplant. The present findings suggest a disproportionate HLA-G expression after two different anti-proliferative strategies, namely RAD or MMF.…”

Hypoxia induces Wee1 expression and attenuates hydrogen peroxide-induced endothelial damage in MS1 cells

“…Hypoxic conditions may profoundly affect endothelial cells through a cascade of reactions involving neutrophils (Sumagin et al, 2006(Sumagin et al, , 2008Butler et al, 2008;Carpenter and Alexander, 2008;Hu et al, 2008) and smooth muscle cells (Michiels et al, 2000;Aley et al, 2008;Jernigan et al, 2008;Mayr et al, 2008;Osada-Oka et al, 2008a, 2008bSheshgiri et al, 2008). Hypoxia regulates the expression of many genes, and the list of hypoxiarelated genes is growing (Yoshida et al, 2006;Eckardt et al, 2007;Said et al, 2007;Wang et al, 2007;Chen et al, 2008;Furuta et al, 2008;Yang et al, 2008).…”

Immunobiology of HLA Class-Ib Molecules in Transplantation

“…The MLR shows high levels of cytotoxicity with only one donor, possibly because the recipient's NK-CTLs and those of the donor do not share their HLA-G alleles; but more studies are needed to elucidate this point. HLA-E loaded with a peptide derived from the leader sequence of allogeneic HLA-G molecules (expressed in the allograft cells) can be recognized by CD8+ T cells by means of their TCR, inducing the activation of cytotoxicity, the secretion of cytokines, and eventually the production of antibodies, which leads to graft rejection-all, as shown in Figure 2. HLA-G was shown to be expressed by endothelial cells and its expression and secretion upregulated in a dose-dependent manner by progesterone [79]. The induction of HLA-G expression in endothelial cells of the allograft can clearly benefit the patient by inhibiting effector cells responsible for rejection and vasculopathy.…”