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IFNgamma regulates PDGF-receptor alpha expression in macrophages, THP-1 cells, and arterial smooth muscle cells
Paula I Morelli1, Sofia Martinsson, Gunnel Ostergren-Lundén
1The Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden. paula.morelli@medkem.gu.se
Abstract:
The recruitment of monocyte-derived macrophages (MDMs) and arterial smooth muscle cells (ASMCs) contributes to inflammation and development of intimal hyperplasia during atherosclerosis. Platelet-derived growth factor (PDGF) is a potent mitogen for SMC, signalling through PDGF-receptor subunits alpha (Ralpha) and beta (Rbeta). We have previously found that interferon gamma (IFNgamma) upregulates PDGF-Ralpha mRNA expression in human MDM (hMDM) which causes an increased migration towards PDGF. In the present study, we found that IFNgamma mediated an upregulation of PDGF-Ralpha mRNA also in THP-1 cells. The induction of PDGF-Ralpha in both hMDM and THP-1 cells was caused by STAT1 binding to the PDGF-Ralpha promoter. In human ASMCs, IFNgamma again stimulated a transient STAT1-binding to the PDGF-Ralpha promoter. However, this was not followed by an upregulation of PDGF-Ralpha mRNA. IFNgamma-stimulation resulted in augmented expression of PDGF-Ralpha protein in differentiated hMDM. Early hMDM only expressed an immature and not fully glycosylated form of the PDGF-Ralpha protein. In contrast, THP-1 cells did not synthesize PDGF-Ralpha protein, implying further posttranscriptional inhibition. Our results contribute to a better understanding of the complex regulation of PDGF-Ralpha expression and how proinflammatory factors may contribute to PDGF-related hyperplasia in vascular diseases.
Insights
Interferon gamma (IFNγ) upregulates platelet-derived growth factor receptor alpha (PDGF-Rα) in macrophages via STAT1, impacting vascular hyperplasia. This study clarifies PDGF-Rα regulation in inflammatory conditions like atherosclerosis.
Area of Science:
- Molecular Biology
- Immunology
- Cardiovascular Research
Background:
- Monocyte-derived macrophages (MDMs) and arterial smooth muscle cells (ASMCs) drive atherosclerosis inflammation and intimal hyperplasia.
- Platelet-derived growth factor (PDGF) promotes smooth muscle cell (SMC) proliferation, signaling via PDGF receptors (PDGF-Rα and PDGF-Rβ).
- Previous work showed interferon gamma (IFNγ) increases PDGF-Rα mRNA in human MDMs (hMDMs), enhancing migration.
Purpose of the Study:
- To investigate IFNγ's role in regulating PDGF-Rα expression in macrophages and ASMCs.
- To elucidate the molecular mechanisms, including STAT1 involvement, underlying PDGF-Rα modulation by IFNγ.
- To understand how these inflammatory pathways contribute to PDGF-related hyperplasia in vascular diseases.
Main Methods:
- Analysis of PDGF-Rα mRNA and protein expression in hMDMs and THP-1 cells stimulated with IFNγ.
- Investigation of STAT1 binding to the PDGF-Rα promoter using chromatin immunoprecipitation assays.
- Assessment of PDGF-Rα protein glycosylation and synthesis in different cell types.
Main Results:
- IFNγ upregulated PDGF-Rα mRNA in both hMDMs and THP-1 cells, mediated by STAT1 binding to the promoter.
- In ASMCs, IFNγ induced transient STAT1 binding but not PDGF-Rα mRNA upregulation.
- Differentiated hMDMs showed increased PDGF-Rα protein, while THP-1 cells exhibited posttranscriptional inhibition of protein synthesis.
Conclusions:
- IFNγ differentially regulates PDGF-Rα expression in immune and vascular cells via STAT1-dependent transcriptional mechanisms.
- Posttranscriptional events significantly impact PDGF-Rα protein levels, particularly in THP-1 cells.
- Findings enhance understanding of PDGF-Rα regulation and the contribution of inflammatory factors to vascular hyperplasia.
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