Tumor necrosis factor-alpha induces VCAM-1-mediated inflammation via c-Src-dependent transactivation of EGF receptors in human cardiac fibroblasts.

Chih-Chung Lin,Chuen-Mao Yang,Chih-Shuo Pan,Li-Der Hsiao,Chen-Yu Wang,Shiau-Wen Liu

doi:10.1186/s12929-015-0165-8

Abstract

BackgroundTumor necrosis factor-α (TNF-α) is a proinflammatory cytokine and elevated in the regions of tissue injury and inflammatory diseases. The deleterious effects of TNF-α on fibroblasts may aggravate heart inflammation mediated through the up-regulation of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1). However, the mechanisms underlying TNF-α-induced VCAM-1 expression in cardiac fibroblasts remain unknown. This study aimed to investigate the roles of TNF-α in VCAM-1 expression and its effects on human cardiac fibroblasts (HCFs).ResultsThe primary culture HCFs were used in this study. The results obtained with Western blotting, real time-quantitative PCR, and promoter activity analyses showed that TNF-α-induced VCAM-1 expression was mediated through TNF receptor (TNFR) 1-dependent gene up-regulation. Activation of TNFR1 by TNF-α transactivated c-Src-dependent EGF receptor (EGFR) linking to PI3K/Akt cascade, and then led to transcriptional activity of NF-κB. Moreover, the results of promoter reporter assay demonstrated that the phosphorylated p65 NF-κB turned on VCAM-1 gene expression. Subsequently, up-regulation of VCAM-1 promoted monocytes adhesion to HCFs challenged with TNF-α determined by cell adhesion assay.ConclusionsTaken together, these results indicate that in HCFs, activation of NF-κB by c-Src-mediated transactivation of EGFR/PI3K/Akt cascade is required for TNF-α-induced VCAM-1 expression. Finally, increased VCAM-1 enhances monocytes adhering to HCFs challenged with TNF-α. Understanding the mechanisms of VCAM-1 up-regulated by TNF-α on HCFs may provide rationally therapeutic interventions for heart injury or inflammatory diseases.

Highlights

Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine and elevated in the regions of tissue injury and inflammatory diseases
TNF-α induces vascular cell adhesion molecule-1 (VCAM-1) expression and monocyte adhesion To evaluate the effect of TNF-α on vascular cell adhesion molecule (VCAM)-1 protein and mRNA expression, human cardiac fibroblasts (HCFs) were incubated with various concentrations of TNF-α for the indicated time intervals
We found that 30 ng/ml TNF-α induced a maximal VCAM-1 induction within 16–24 h

Summary

Introduction

Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine and elevated in the regions of tissue injury and inflammatory diseases. The previous study indicates that pathological fibrosis has emerged as a key target for pharmacological intervention in heart failure [4] Several proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) are elevated in acute myocardial injury and infarction. Elevated these cytokines have been shown to cause phenotypic and functional changes in the constituent cell types of the heart [5,6,7,8], including cell proliferation, production of the collagen extracellular matrix (ECM), generation of mediator substances by the cardiac fibroblast [9,10,11], and associate with heart failure [12].

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