Interferon‐γ promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin (ET)‐1 and transforming growth factor (TGF) β2

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.

Celecoxib, but not indomethacin, ameliorates the hypertensive and perivascular fibrotic actions of cyclosporine in rats: Role of endothelin signaling

“…The increased renovascular fibrosis caused by CSA is consistent with reported studies, which related CSA hypertension to vascular structural derangements including perivascular fibrosis (Lassila et al, 2001;Rezzani et al, 2005). Pertinent observations include the following: (i) reported studies including ours showed that enhanced ET/ transforming growth factor-beta1 (TGF-β1) signaling mediates tissue fibrosis caused by CSA (Chatziantoniou and Dussaule, 2000;El-Gowelli et al, 2014), (ii) ET B receptors reduce TGF-β1 and subsequently attenuate hypertension and renal failure progression in uremic animals (Lavoie et al, 2005), (iii) the ET/ET A receptor signaling promotes the TGF-β1-induced renal fibrosis (Chrobak et al, 2013), and (iv) celecoxib prevents and reverses liver fibrosis induced by carbon tetrachloride via decreasing TGF-β1 expression (Chávez et al, 2010). That said, it is plausible to suggest that the renovascular antifibrotic effect of celecoxib, triggered possibly by the increased ET B and decreased ET A receptor expression, contributed to the BP lowering effect of celecoxib in CSA-treated rats.…”

Epigenetic suppression of Fli1, a potential predisposing factor in the pathogenesis of systemic sclerosis

“…On the other hand, interferon-␣ and interferon-␥ suppress mRNA levels of FLI1 gene in dermal microvascular endothelial cells and lipopolysaccharide stimulation reduces mRNA expression of FLI1 gene in macrophages (Chrobak et al, 2013;Ho and Ivashkiv, 2010). Thus, Fli1 expression is regulated at transcriptional and/or posttranslational levels in cell type-and context-dependent manners.…”

Immunology of Psoriasis

“…Numerous immune molecules were elevated in the circulation but without elevation in corresponding skin mRNA, including IL-16, IL-18, and CD40 ligand. PAI1 is a product of inflamed endothelial cells (120), that could be induced by cytokines increased in the blood. Leptin, the hormone associated with obesity, was 1.5 log 2 (FCH) times higher in psoriasis patients versus healthy volunteers, and higher in psoriasis patients with BMI >30 (mean 24 ng/ml) versus psoriasis patients with BMI <30 (mean 7 ng/ml) (119).…”