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

Background: tumor 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). results: the 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. conclusions: taken 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. © 2015 lin et al.