Interferon‐γ promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin (ET)‐1 and transforming growth factor (TGF) β2
- 28 January 2013
- journal article
- research article
- Published by Wiley in Journal of Cellular Physiology
- Vol. 228 (8), 1774-1783
- https://doi.org/10.1002/jcp.24337
Abstract
Systemic sclerosis (SSc) is a complex disease characterized by vascular alterations, activation of the immune system and tissue fibrosis. Previous studies have implicated activation of the interferon pathways in the pathogenesis of SSc. The goal of this study was to determine whether interferon type I and/or type II could play a pathogenic role in SSc vasculopathy. Human dermal microvascular endothelial cells (HDMVECs) and fibroblasts were obtained from foreskins of healthy newborns. The RT Profiler PCR Array System was utilized to screen for EndoMT genes. Treatment with IFN‐α or IFN‐γ downregulated Fli1 and VE‐cadherin. In contrast, IFN‐α and IFN‐γ exerted opposite effects on the expression of α‐SMA, CTGF, ET‐1, and TGFβ2, with IFN‐α downregulating and IFN‐γ upregulating this set of genes. Blockade of TGFβ signaling normalized IFN‐γ‐mediated changes in Fli1, VE‐cadherin, CTGF, and ET‐1 levels, whereas upregulation of α‐SMA and TGFβ2 was not affected. Bosentan treatment was more effective than TGFβ blockade in reversing the actions of IFN‐γ, including downregulation of α‐SMA and TGFβ2, suggesting that activation of the ET‐1 pathway plays a main role in the IFN‐γ responses in HDMECs. IFN‐γ induced expression of selected genes related to endothelial‐to‐mesenchymal transition (EndoMT), including Snail1, FN1, PAI1, TWIST1, STAT3, RGS2, and components of the WNT pathway. The effect of IFN‐γ on EndoMT was mediated via TGFβ2 and ET‐1 signaling pathways. This study demonstrates distinct effects of IFN‐α and IFN‐γ on the biology of vascular endothelial cells. IFN‐γ may contribute to abnormal vascular remodeling and fibrogenesis in SSc, partially via induction of EndoMT. J. Cell. Physiol. 228: 1774–1783, 2013.Funding Information
- NIH NIAMS (RO1 AR42334, RO1AR44883)
This publication has 49 references indexed in Scilit:
- Inflammation-Induced Endothelial-to-Mesenchymal Transition: A Novel Mechanism of Intestinal FibrosisThe American Journal of Pathology, 2011
- Role of Endothelial-Mesenchymal Transition (EndoMT) in the Pathogenesis of Fibrotic DisordersThe American Journal of Pathology, 2011
- Vascular involvement in systemic sclerosis (scleroderma)Journal of Inflammation Research, 2011
- Protein kinase Cδ and c‐Abl kinase are required for transforming growth factor β induction of endothelial–mesenchymal transition in vitroArthritis & Rheumatism, 2011
- Dysregulated expression of MIG/CXCL9, IP-10/CXCL10 and CXCL16 and their receptors in systemic sclerosisArthritis Research & Therapy, 2011
- Conversion of vascular endothelial cells into multipotent stem-like cellsNature Medicine, 2010
- Innate immunity and inflammation in systemic sclerosisCurrent Opinion in Rheumatology, 2009
- Cross-regulation of Signaling Pathways by Interferon-γ: Implications for Immune Responses and Autoimmune DiseasesImmunity, 2009
- Cytokine regulation of tight junctionsBiochimica et Biophysica Acta (BBA) - Biomembranes, 2009
- Capillary Regeneration in Scleroderma: Stem Cell Therapy Reverses Phenotype?PLOS ONE, 2008