Document Detail


Interferon-γ promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin (ET)-1 and transforming growth factor (TGF) β2.
MedLine Citation:
PMID:  23359533     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Izabela Chrobak; Stefania Lenna; Lukasz Stawski; Maria Trojanowska
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of cellular physiology     Volume:  228     ISSN:  1097-4652     ISO Abbreviation:  J. Cell. Physiol.     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-04-22     Completed Date:  2013-06-24     Revised Date:  2014-06-29    
Medline Journal Info:
Nlm Unique ID:  0050222     Medline TA:  J Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1774-83     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Wiley Periodicals, Inc.
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MeSH Terms
Descriptor/Qualifier:
Cells, Cultured
Endothelial Cells / metabolism*
Endothelin-1 / genetics,  metabolism*
Endothelium, Vascular / cytology*,  metabolism*
Fibrosis
Humans
Interferon-gamma / physiology*
Scleroderma, Systemic / etiology,  pathology,  physiopathology
Transforming Growth Factor beta2 / genetics,  metabolism*
Up-Regulation / drug effects
Grant Support
ID/Acronym/Agency:
P50 AR060780/AR/NIAMS NIH HHS; R01 AR042334/AR/NIAMS NIH HHS; R01 AR044883/AR/NIAMS NIH HHS; R01 AR42334/AR/NIAMS NIH HHS; R01AR44883/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Endothelin-1; 0/Transforming Growth Factor beta2; 82115-62-6/Interferon-gamma
Comments/Corrections

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