ATF4 is a novel regulator of MCP-1 in microvascular endothelial cells

Journal of Inflammation

Research

Guangjun Jing¹  Nader Sheibani²  Huibin Huang³  Sarah X Zhang⁴  Joshua J Wang⁴ 

[1] Department of Medicine, Endocrinology and Diabetes, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, 73104, Oklahoma, OK, USA;Department of Ophthalmology and Visual Sciences, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA;McPherson Eye Research Institute, University of Wisconsin, School of Medicine and Public Health, 53705, Madison, WI, USA;Departments of Ophthalmology and Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 14214, Buffalo, NY, USA;SUNY Eye Institute, The State University of New York, 14214, Buffalo, NY, USA;Department of Endocrinology, The 2nd Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China;Departments of Ophthalmology and Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 14214, Buffalo, NY, USA;SUNY Eye Institute, The State University of New York, 14214, Buffalo, NY, USA;Department of Medicine, Endocrinology and Diabetes, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, 73104, Oklahoma, OK, USA;

关键词: Monocyte chemoattractant protein 1;    Microvascular endothelial cells;    Activating transcription factor 4;   

DOI  :  10.1186/s12950-015-0076-1

 received in 2015-01-06, accepted in 2015-03-31,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundMonocyte chemoattractant protein-1 (MCP-1) is a major chemokine that recruits monocyte/macrophage to the site of tissue injury and plays a critical role in microvascular complications of diabetes. However, the mechanisms underlying the regulation of MCP-1 are not fully understood. The present study aims to explore the role of activating transcription factor 4 (ATF4), an ER stress-inducible transcription factor, in regulation of MCP-1 expression and production in brain and retinal microvascular endothelial cells.MethodsFor in vitro study, primary brain microvascular endothelial cells isolated from ATF4 knockout mice or mouse retinal endothelial cells were treated with lipopolysaccharide (LPS) to induce MCP-1 expression. ATF4 expression/function was manipulated by adenoviruses expressing wild type ATF4 (Ad-ATF4) or a dominant negative mutant of the protein (Ad-ATF4DN). For in vivo study, MCP-1 expression was induced by intravitreal injection of LPS or Ad-ATF4 in heterozygous ATF4 knockout or wild type mice.ResultsLPS treatment induced a dose- and time-dependent increase in ATF4 expression, ER stress and MCP-1 production in brain and retinal microvascular endothelial cells. Overexpression of ATF4 in endothelial cells significantly increased the secretion of MCP-1 and promoted THP-1 monocyte-endothelial cell adhesion. Conditioned medium from ATF4-overexpressiing endothelial cells significantly enhanced THP-1 cell migration. Consistently, intravitreal injection of Ad-ATF4 remarkably enhanced retinal levels of MCP-1 and promoted inflammatory cell infiltration into the vitreous and retina. In contrast, LPS-induced MCP-1 upregulation was markedly attenuated in ATF4-deficient endothelial cells and in retinas of ATF4 knockout mice, suggesting that ATF4 is essential for LPS-induced MCP-1 production in endothelial cells and in the retina. Mechanistically, overexpression of ATF4 enhanced, while inhibition of ATF4, attenuated the basal and LPS-stimulated phosphorylation of NF-κB, P38, and JNK. Furthermore, pharmacological inhibition of NF-κB, P38, or JNK significantly reduced ATF4-stimulated MCP-1 secretion from endothelial cells.ConclusionsTaken together, our results suggest a critical role of ATF4 in the regulation of MCP-1 production in retinal and brain microvascular endothelial cells, which may contribute to inflammation-related endothelial injury in diseases such as diabetic retinopathy.

【 授权许可】

Unknown   
© Huang et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.