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Progesterone induces human leukocyte antigen-g expression in vascular endothelial and smooth muscle cells
Rohit Sheshgiri1, Vivek Rao, Laura C Tumiati
1MSc, NCSB 11C-1201, Toronto General Hospital, 585 University Avenue, Toronto, Ontario, Canada.
Insights
Progesterone can induce human leukocyte antigen-G (HLA-G) expression in vascular cells, offering a potential therapeutic strategy for heart transplant rejection. This finding may help prevent allograft vasculopathy and rejection.
Area of Science:
- Immunology
- Transplantation Biology
- Vascular Biology
Background:
- Human leukocyte antigen-G (HLA-G) expression is linked to reduced acute cellular rejection and cardiac allograft vasculopathy in heart transplant recipients.
- Investigating HLA-G induction in vascular cells could reveal new therapeutic targets for preventing transplant complications.
Purpose of the Study:
- To determine if HLA-G expression can be induced in human vascular endothelial and smooth muscle cells.
- To explore potential therapeutic agents for enhancing HLA-G expression to protect against heart transplant rejection and vasculopathy.
Main Methods:
- Human coronary artery endothelial, aortic endothelial, and coronary artery smooth muscle cells were cultured.
- Cells were exposed to cytokines (interferon-gamma, interleukin-10), hypoxia/reoxygenation, immunosuppressants (cyclosporine, sirolimus, tacrolimus), or progesterone.
- HLA-G expression was measured using enzyme-linked immunosorbent assay and flow cytometry.
Main Results:
- Progesterone dose-dependently induced HLA-G expression in all tested vascular cell types without affecting viability or proliferation.
- Cytokines, hypoxia/reoxygenation, and immunosuppressive agents did not induce HLA-G expression.
- Progesterone's effect was partially inhibited by mifepristone, a progesterone receptor antagonist.
Conclusions:
- Vascular endothelial and smooth muscle cells do not express HLA-G at baseline but can be induced by progesterone.
- Progesterone-induced HLA-G expression represents a potential novel therapeutic strategy for heart transplant recipients.
- Further research is needed to confirm the protective role of induced HLA-G against transplant rejection and vasculopathy.
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-gamma 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-gamma, 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 (P<0.001) 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: 48.8+/-15.6%; human coronary aortic endothelial: 59.5+/-9.5%; human coronary artery smooth muscle: 59.8+/-9.8% of control; P<0.05). 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.
