title: Tumor necrosis factor-alpha induces VCAM-1-mediated inflammation via c-Src-dependent transactivation of EGF receptors in human cardiac fibroblasts.
abstract: 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.
authors.affiliation: Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo, Kwei-Shan, Tao-Yuan, Taiwan.|College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan.
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Department of Physiology, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan.|Department of Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, Taiwan.
authors.forename: Chih-Shuo
authors.initials: CS
authors.lastname: Pan
authors.affiliation: Department of Physiology, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan.|Department of Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, Taiwan.
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo, Kwei-Shan, Tao-Yuan, Taiwan.|College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan.
authors.forename: Shiau-Wen
authors.initials: SW
authors.lastname: Liu
authors.affiliation: Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo, Kwei-Shan, Tao-Yuan, Taiwan.|College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan.
authors.forename: Li-Der
authors.initials: LD
authors.lastname: Hsiao
authors.affiliation: Department of Physiology, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan. chuenmao@mail.cgu.edu.tw.|Department of Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, Taiwan. chuenmao@mail.cgu.edu.tw.
authors.forename: Chuen-Mao
authors.initials: CM
authors.lastname: Yang
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D066246:ErbB Receptors / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases; D061251:Primary Cell Culture; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D019061:src-Family Kinases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D066246:ErbB Receptors; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D019061:src-Family Kinases; C512478:EGFR protein, human; C000631346:CSK protein, human